Is APC p.Glu658Val (c.1973A>T) pathogenic?

APC p.Glu658Val (c.1973A>T) is classified Uncertain significance in APC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-07-15). AlphaMissense: ambiguous (0.4316); Very rare (popmax 0.000254%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with APC p.Glu658Val (c.1973A>T)?

APC p.Glu658Val (c.1973A>T) is associated with hereditary neoplastic syndrome, familial adenomatous polyposis 1 (ClinVar).

How common is APC p.Glu658Val (c.1973A>T) in the general population?

APC p.Glu658Val (c.1973A>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about APC p.Glu658Val (c.1973A>T)?

AlphaMissense predicts ambiguous (score 0.4316) — an in-silico prediction, not a clinical call.

APC p.Glu658Val

c.1973A>T · rs777980327 · VCV1462404

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4316 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.4316	ambiguous
REVEL	0.583	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.8, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 11 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	23.8	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,178,876 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,612,710 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: APC
Protein: p.Glu658Val
Coding: c.1973A>T
MANE Select: NM_000038
dbSNP: rs777980327
Type: single nucleotide variant
Location: chr5:112837567 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 658: an α-helix

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial adenomatous polyposis 1

Similar variants

APC p.Glu658Gln Uncertain significance ★★ same residue
APC p.Glu658Lys Uncertain significance ★★ same residue
APC p.Glu658= Benign/Likely benign ★★ same residue
APC p.Glu658Gly Uncertain significance ★ same residue
APC p.Glu658fs Pathogenic ★★ same residue
APC p.Glu658Met Uncertain significance ★★ same residue
APC p.Glu658_Asn659insLys Uncertain significance ★ same residue
APC c.1312+3A>C 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-glu658val (accessed [today's date]).

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