Is APOBEC2 p.Val74Ala (c.221T>C) pathogenic?

APOBEC2 p.Val74Ala (c.221T>C) is classified Uncertain significance in APOBEC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-08). AlphaMissense: likely pathogenic (0.5802); Very rare (popmax 0.00503%, amr).

How common is APOBEC2 p.Val74Ala (c.221T>C) in the general population?

APOBEC2 p.Val74Ala (c.221T>C) is very rare (popmax 0.00503%, amr) (gnomAD).

What do computational predictors say about APOBEC2 p.Val74Ala (c.221T>C)?

AlphaMissense predicts likely pathogenic (score 0.5802) — an in-silico prediction, not a clinical call.

APOBEC2 p.Val74Ala

c.221T>C · VCV4641694

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5802 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00503%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5802	likely pathogenic
REVEL	0.801	moderately pathogenic-leaning
SaProt	LLR -9.96	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.2, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 8,520 bp · p 0.1 · regional, not allelic
Overall
CADD	24.5	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 0.00503% Admixed American · 3/59,662 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00067%

Overall 0.000686% 10/1,458,276 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00503%	19,887
South Asian	0.00221%	45,194
Remaining individualsnot grpmax-eligible	0.0016%	62,338
European (non-Finnish)	0.000339%	294,580

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: APOBEC2
Protein: p.Val74Ala
Coding: c.221T>C
MANE Select: NM_006789
Type: single nucleotide variant
Location: chr6:41061417 (GRCh38)
Gene constraint: LOEUF 1.085 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.10 · 1 PDB
Residue 74: the cmp/dcmp-type deaminase domain; a β-strand

Full APOBEC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APOBEC2 p.Ala2Asp Uncertain significance ★ ⚠ same type
APOBEC2 p.Ala8Val Uncertain significance ★ ⚠ same type
APOBEC2 p.Ala95Val Uncertain significance ★ ⚠ same type
APOBEC2 p.Arg116Trp Uncertain significance ★ ⚠ same type
APOBEC2 p.Arg46Gln Uncertain significance ★ ⚠ same type
APOBEC2 p.Arg46Trp Uncertain significance ★ ⚠ same type
APOBEC2 p.Arg57Trp Uncertain significance ★ ⚠ same type
APOBEC2 p.Arg87Trp 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/apobec2-p-val74ala (accessed [today's date]).

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