Is APC p.Val543Phe (c.1627G>T) pathogenic?

APC p.Val543Phe (c.1627G>T) is classified Uncertain significance in APC (ClinVar, Expert panel, 4 submitters; last evaluated 2023-02-19). AlphaMissense: likely pathogenic (0.9936); Absent from gnomAD v4.1; Associated with familial adenomatous polyposis 1.

What condition is associated with APC p.Val543Phe (c.1627G>T)?

APC p.Val543Phe (c.1627G>T) is associated with familial adenomatous polyposis 1, hereditary neoplastic syndrome (ClinVar).

How common is APC p.Val543Phe (c.1627G>T) in the general population?

APC p.Val543Phe (c.1627G>T) is absent from gnomAD v4.1 (gnomAD).

How is Familial adenomatous polyposis inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about APC p.Val543Phe (c.1627G>T)?

AlphaMissense predicts likely pathogenic (score 0.9936) — an in-silico prediction, not a clinical call.

APC p.Val543Phe

c.1627G>T · rs1554082080 · VCV490221

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9936 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

familial adenomatous polyposis 1

ClinGen expert panel — InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP

Uncertain Significance for familial adenomatous polyposis 1. Applied ACMG criteria (verbatim):

PM2_Supporting PS3_Moderate BP1

Curation rationale (ClinGen, verbatim)

The c.1627G>T variant in APC is a missense variant predicted to cause a substitution of valine by phenylalanine at amino acid position 543 (p.Val543Phe). This variant is located at the first base of exon 14. RT-PCR of the exons flanking the target site in a patient with AFAP shows that the variant c.1627G>T impacts splicing by leading to exon 14 skipping, which is an in-frame event (PS3_Moderate; PMID22987206). This variant scored 0.5 phenotype points based on information available in 3 individuals (PS4_variable not met; PMID 22987206, Invitae internal data). This variant is absent from gnomAD v2.1.1 (PM2_supporting). In silico predictions by SpliceAI, MaxEntScan and VarSEAK showed conflicting results (PP3 not met). APC is defined by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) as a gene for which primarily truncating variants are known to cause disease (BP1). In summary, this is a Variant of Uncertain Significance (VUS) for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BP1, PS3_moderate, and PM2_supporting. (VCEP specifications version 1; date of approval: 12/12/2022).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.9936	likely pathogenic · top 5% in APC
REVEL	0.768	pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.6, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 11 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: APC
Protein: p.Val543Phe
Coding: c.1627G>T
MANE Select: NM_000038
dbSNP: rs1554082080
Type: single nucleotide variant
Location: chr5:112828856 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 543: an α-helix

Full APC gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

familial adenomatous polyposis 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome

For Familial adenomatous polyposis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Adult
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

APC p.Val543= Benign/Likely benign ★★ same residue
APC p.Val543Ala Uncertain significance ★ ⚠ same residue
APC p.Val543Ile Uncertain significance ★ same residue
APC c.1312+3A>C Likely pathogenic ★★★ same condition
APC c.1312+3A>G Pathogenic ★★★ same condition
APC c.1312+5G>A Likely pathogenic ★★★ same condition
APC c.1312+5G>C Likely pathogenic ★★★ same condition
APC c.1409-3T>G Likely pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/apc-p-val543phe (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown