Is APBB2 p.Pro312Ala (c.934C>G) pathogenic?

APBB2 p.Pro312Ala (c.934C>G) is classified Uncertain significance in APBB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-15). AlphaMissense: ambiguous (0.4856); Ultra-rare (popmax 0.0187%, afr).

How common is APBB2 p.Pro312Ala (c.934C>G) in the general population?

APBB2 p.Pro312Ala (c.934C>G) is ultra-rare (popmax 0.0187%, afr) (gnomAD).

What do computational predictors say about APBB2 p.Pro312Ala (c.934C>G)?

AlphaMissense predicts ambiguous (score 0.4856) — an in-silico prediction, not a clinical call.

APBB2 p.Pro312Ala

c.934C>G · rs375419961 · VCV2249430

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4856 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4856	ambiguous
REVEL	0.709	pathogenic-leaning
SaProt	LLR -8.47	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.9, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 217 kb · p 1.3e-10 · regional, not allelic
Overall
CADD	24.8	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P311A vs ClinVar P312A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0187% African / African-American · 14/74,808 alleles

Filtering AF 0.0112% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00906%

Overall 0.00093% 15/1,613,642 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0187%	5,343
European (non-Finnish)	8.47e-05%	1,179,954

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: APBB2
Protein: p.Pro312Ala
Coding: c.934C>G
MANE Select: NM_004307
dbSNP: rs375419961
Type: single nucleotide variant
Location: chr4:40944975 (GRCh38)
Gene constraint: LOEUF 0.54 · pLI 0.61 (gnomAD)
Structure: AlphaFold pLDDT 61.73
Residue 312: the ww domain

Full APBB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APBB2 c.20-6C>T Benign ★★ same type
APBB2 p.Ala111Val Uncertain significance ★ ⚠ same type
APBB2 p.Ala126Val Uncertain significance ★ ⚠ same type
APBB2 p.Ala197Val Uncertain significance ★ ⚠ same type
APBB2 p.Ala224Asp Uncertain significance ★ ⚠ same type
APBB2 p.Ala279Val Uncertain significance ★ same type
APBB2 p.Ala436Pro Uncertain significance ★ ⚠ same type
APBB2 p.Ala436Thr Uncertain significance ★ ⚠ same type

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/apbb2-p-pro312ala (accessed [today's date]).

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