Is APC2 p.Val720Met (c.2158G>A) pathogenic?

APC2 p.Val720Met (c.2158G>A) is classified Uncertain significance in APC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-13). AlphaMissense: likely benign (0.2391); Very rare (popmax 0.00246%, eas); Associated with Inborn genetic diseases.

What condition is associated with APC2 p.Val720Met (c.2158G>A)?

APC2 p.Val720Met (c.2158G>A) is associated with Inborn genetic diseases (ClinVar).

How common is APC2 p.Val720Met (c.2158G>A) in the general population?

APC2 p.Val720Met (c.2158G>A) is very rare (popmax 0.00246%, eas) (gnomAD).

What do computational predictors say about APC2 p.Val720Met (c.2158G>A)?

AlphaMissense predicts likely benign (score 0.2391) — an in-silico prediction, not a clinical call.

APC2 p.Val720Met

c.2158G>A · VCV4583172

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2391 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00246%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2391	likely benign
REVEL	0.388	indeterminate
SaProt	LLR -6.78	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Overall
CADD	23.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00246% East Asian · 1/40,646 alleles

Filtering AF 8.2e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.5e-05%

Overall 0.000391% 6/1,533,540 alleles · very rare exomes 6/1,381,194 · genomes 0/152,346 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00246%	40,646
South Asian	0.00119%	84,230
European (non-Finnish)	0.000349%	286,364

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.Val720Met
Coding: c.2158G>A
MANE Select: NM_005883
Type: single nucleotide variant
Location: chr19:1465459 (GRCh38)
Gene constraint: LOEUF 0.961 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 48.87
Residue 720: 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-val720met (accessed [today's date]).

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