Is APC2 p.Ala461Val (c.1382C>T) pathogenic?

APC2 p.Ala461Val (c.1382C>T) is classified Uncertain significance in APC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-31). AlphaMissense: likely pathogenic (0.8069); Ultra-rare (popmax 0.015%, amr); Associated with Inborn genetic diseases.

What condition is associated with APC2 p.Ala461Val (c.1382C>T)?

APC2 p.Ala461Val (c.1382C>T) is associated with Inborn genetic diseases (ClinVar).

How common is APC2 p.Ala461Val (c.1382C>T) in the general population?

APC2 p.Ala461Val (c.1382C>T) is ultra-rare (popmax 0.015%, amr) (gnomAD).

What do computational predictors say about APC2 p.Ala461Val (c.1382C>T)?

AlphaMissense predicts likely pathogenic (score 0.8069) — an in-silico prediction, not a clinical call.

APC2 p.Ala461Val

c.1382C>T · rs758805322 · VCV1360121

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8069 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8069	likely pathogenic
REVEL	0.538	indeterminate
SaProt	LLR -9.26	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Overall
CADD	29.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.015% Admixed American · 9/60,008 alleles

Filtering AF 0.00773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00578%

Overall 0.0013% 21/1,613,418 alleles · ultra-rare exomes 15/1,461,170 · genomes 6/152,248 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.015%	6,668
Remaining individualsnot grpmax-eligible	0.0048%	20,827
African / African-American	0.004%	24,981
European (non-Finnish)	0.000508%	196,671

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: APC2
Protein: p.Ala461Val
Coding: c.1382C>T
MANE Select: NM_005883
dbSNP: rs758805322
Type: single nucleotide variant
Location: chr19:1460259 (GRCh38)
Gene constraint: LOEUF 0.961 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 48.87
Residue 461: a UniProt-annotated variant site (in cdcbm10)

Full APC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

APC2 p.Ala1059Glu Uncertain significance ★★ ⚠ same condition
APC2 p.Ala1103Thr Uncertain significance ★★ ⚠ same condition
APC2 p.Ala1116Val Uncertain significance ★★ ⚠ same condition
APC2 p.Ala126Ser Uncertain significance ★★ ⚠ same condition
APC2 p.Ala1311Thr Uncertain significance ★★ ⚠ same condition
APC2 p.Ala1359Val Uncertain significance ★★ ⚠ same condition
APC2 p.Ala1438Thr Uncertain significance ★★ ⚠ same condition
APC2 p.Ala1492Glu Uncertain significance ★★ ⚠ 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/apc2-p-ala461val (accessed [today's date]).

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