Is APBB2 p.Ile303Ser (c.908T>G) pathogenic?

APBB2 p.Ile303Ser (c.908T>G) is classified Uncertain significance in APBB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-13). AlphaMissense: likely benign (0.1841); Ultra-rare (popmax 0.0177%, mid).

How common is APBB2 p.Ile303Ser (c.908T>G) in the general population?

APBB2 p.Ile303Ser (c.908T>G) is ultra-rare (popmax 0.0177%, mid) (gnomAD).

What do computational predictors say about APBB2 p.Ile303Ser (c.908T>G)?

AlphaMissense predicts likely benign (score 0.1841) — an in-silico prediction, not a clinical call.

APBB2 p.Ile303Ser

c.908T>G · VCV4117792

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1841 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0177%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1841	likely benign
REVEL	0.364	indeterminate
SaProt	LLR -10.58	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 217 kb · p 1.3e-10 · regional, not allelic
Overall
CADD	22.7	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 I302S vs ClinVar I303S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0177% Middle Eastern · 1/5,664 alleles

Filtering AF 0.00277% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000458% 7/1,529,776 alleles · ultra-rare exomes 6/1,383,726 · genomes 1/146,050 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0177%	5,664
African / African-American	0.00707%	14,140
Remaining individualsnot grpmax-eligible	0.00175%	57,218

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.Ile303Ser
Coding: c.908T>G
MANE Select: NM_004307
Type: single nucleotide variant
Location: chr4:40945001 (GRCh38)
Gene constraint: LOEUF 0.54 · pLI 0.61 (gnomAD)
Structure: AlphaFold pLDDT 61.73
Residue 302 UniProt numbering: 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-ile303ser (accessed [today's date]).

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