Is APC p.Ala199Val (c.596C>T) pathogenic?

APC p.Ala199Val (c.596C>T) is classified Uncertain significance in APC (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-04-28). AlphaMissense: likely benign (0.2977); Very rare (popmax 0.00659%, sas); Associated with classic or attenuated familial adenomatous polyposis.

What condition is associated with APC p.Ala199Val (c.596C>T)?

APC p.Ala199Val (c.596C>T) is associated with classic or attenuated familial adenomatous polyposis, hereditary neoplastic syndrome, familial adenomatous polyposis 1 (ClinVar).

How common is APC p.Ala199Val (c.596C>T) in the general population?

APC p.Ala199Val (c.596C>T) is very rare (popmax 0.00659%, sas) (gnomAD).

What do computational predictors say about APC p.Ala199Val (c.596C>T)?

AlphaMissense predicts likely benign (score 0.2977) — an in-silico prediction, not a clinical call.

APC p.Ala199Val

c.596C>T · rs748193367 · VCV246301

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.2977 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00659%, sas)

Conditions

classic or attenuated familial adenomatous polyposis

Computational evidence

Protein change
AlphaMissense	0.2977	likely benign
REVEL	0.353	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 61 kb · p 0.82 · regional, not allelic
Overall
CADD	25.3	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 · 6/91,010 alleles

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

Overall 0.00112% 18/1,613,090 alleles · very rare exomes 18/1,460,972 · genomes 0/152,118 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00659%	15,168
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,582
Finnishnot grpmax-eligible	0.00313%	31,987
Remaining individualsnot grpmax-eligible	0.0016%	62,474
African / African-American	0.00133%	74,942
European (non-Finnish)	0.000594%	168,481

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.Ala199Val
Coding: c.596C>T
MANE Select: NM_000038
dbSNP: rs748193367
Type: single nucleotide variant
Location: chr5:112780854 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 199: an α-helix

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

Disease context

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

Also linked: hereditary neoplastic syndrome familial adenomatous polyposis 1

Similar variants

APC p.Ala199Gly Uncertain significance ★★ same residue
APC p.Ala199Thr Uncertain significance ★★ ⚠ same residue
APC p.Ala199Glu Uncertain significance ★ same residue
APC p.Ala199= Likely benign ★ same residue
APC p.Ala199fs 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

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-ala199val (accessed [today's date]).

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