Is APC p.Ala41Val (c.122C>T) pathogenic?

APC p.Ala41Val (c.122C>T) is classified Uncertain significance in APC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-26). AlphaMissense: likely pathogenic (0.6845); Very rare (popmax 0.00659%, sas); Associated with familial adenomatous polyposis 1.

What condition is associated with APC p.Ala41Val (c.122C>T)?

APC p.Ala41Val (c.122C>T) is associated with familial adenomatous polyposis 1 (ClinVar).

How common is APC p.Ala41Val (c.122C>T) in the general population?

APC p.Ala41Val (c.122C>T) is very rare (popmax 0.00659%, sas) (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.Ala41Val (c.122C>T)?

AlphaMissense predicts likely pathogenic (score 0.6845) — an in-silico prediction, not a clinical call.

APC p.Ala41Val

c.122C>T · rs1754802758 · VCV2677074

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6845 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00659%, sas)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

familial adenomatous polyposis 1

Computational evidence

Protein change
AlphaMissense	0.6845	likely pathogenic
REVEL	0.275	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense calls this damaging; REVEL does not; SaProt makes no call.
Splicing
SpliceAI	Δ0.93	donor gain · deltas
Pangolin	Δ0.75	gain · loss 0.36 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 2.8, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 61 kb · p 0.82 · regional, not allelic
Overall
CADD	35.0	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 0.00659% South Asian · 6/91,064 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.000372% 6/1,613,432 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.Ala41Val
Coding: c.122C>T
MANE Select: NM_000038
dbSNP: rs1754802758
Type: single nucleotide variant
Location: chr5:112755012 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 41: 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

For Familial adenomatous polyposis (Orphanet):

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

Similar variants

APC p.Ala41= Likely benign ★★★ same residue
APC p.Ala41Glu Uncertain significance ★ same residue
APC p.Ala41Ser Uncertain significance ★ same residue
APC p.Ala41Thr Conflicting classifications of pathogenicity ★ same residue
APC p.Pro41= Uncertain significance ★ same residue
APC p.Pro41Ala Conflicting classifications of pathogenicity ★ same residue
APC p.Pro41Arg Uncertain significance ★ same residue
APC p.Pro41Ser Uncertain significance ★ same residue

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-ala41val (accessed [today's date]).

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