Is APC p.Arg640Trp (c.1918C>T) pathogenic?

APC p.Arg640Trp (c.1918C>T) is classified Uncertain significance in APC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-12). AlphaMissense: likely pathogenic (0.9977); Very rare (popmax 0.00223%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with APC p.Arg640Trp (c.1918C>T)?

APC p.Arg640Trp (c.1918C>T) is associated with hereditary neoplastic syndrome, familial adenomatous polyposis 1, classic or attenuated familial adenomatous polyposis (ClinVar).

How common is APC p.Arg640Trp (c.1918C>T) in the general population?

APC p.Arg640Trp (c.1918C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about APC p.Arg640Trp (c.1918C>T)?

AlphaMissense predicts likely pathogenic (score 0.9977) — an in-silico prediction, not a clinical call.

APC p.Arg640Trp

c.1918C>T · rs1114167575 · VCV428132

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9977 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9977	likely pathogenic · top 3% in APC
REVEL	0.6	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.40 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4	GERP 2.9, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 11 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	28.8	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 0.00223% East Asian · 1/44,854 alleles

Overall 0.000124% 2/1,614,022 alleles · very rare exomes 2/1,461,802 · genomes 0/152,220 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,854
European (non-Finnish)	8.47e-05%	1,179,994

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.Arg640Trp
Coding: c.1918C>T
MANE Select: NM_000038
dbSNP: rs1114167575
Type: single nucleotide variant
Location: chr5:112835125 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 640: 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 classic or attenuated familial adenomatous polyposis

Similar variants

APC p.Arg640Gln Uncertain significance ★★ ⚠ same residue
APC p.Arg640= Likely benign ★★ same residue
APC p.Arg640fs Likely pathogenic ★ 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-arg640trp (accessed [today's date]).

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