Is APOBEC3A p.Arg74Cys (c.220C>T) pathogenic?

APOBEC3A p.Arg74Cys (c.220C>T) is classified Likely benign in APOBEC3A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-03). AlphaMissense: likely benign (0.0586); Very rare (popmax 0.00603%, sas).

How common is APOBEC3A p.Arg74Cys (c.220C>T) in the general population?

APOBEC3A p.Arg74Cys (c.220C>T) is very rare (popmax 0.00603%, sas) (gnomAD).

What do computational predictors say about APOBEC3A p.Arg74Cys (c.220C>T)?

AlphaMissense predicts likely benign (score 0.0586) — an in-silico prediction, not a clinical call.

APOBEC3A p.Arg74Cys

c.220C>T · VCV3934001

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0586 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00603%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0586	likely benign
REVEL	0.107	moderately benign-leaning
SaProt	LLR -5.28	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7.9	GERP -3.2
Regional constraint	o/e 0.16	constrained · MANE · 142 bp · p 1.2e-11 · regional, not allelic
Overall
CADD	0.035	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 0.00603% South Asian · 5/82,882 alleles

Filtering AF 0.00236% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00148%

Overall 0.000955% 13/1,361,764 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00603%	16,576
Remaining individualsnot grpmax-eligible	0.00185%	54,140
European (non-Finnish)	0.000716%	139,576

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: APOBEC3A
Protein: p.Arg74Cys
Coding: c.220C>T
MANE Select: NM_145699
Type: single nucleotide variant
Location: chr22:38961432 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 87.64 · 12 PDB
Residue 74: the cmp/dcmp-type deaminase domain; an α-helix

Full APOBEC3A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APOBEC3B p.Ser109Ala Benign/Likely benign ★★ same type
APOBEC3A p.Ala107Val Uncertain significance ★ ⚠ same type
APOBEC3A p.Ala148Val Uncertain significance ★ ⚠ same type
APOBEC3A p.Ala185Asp Uncertain significance ★ ⚠ same type
APOBEC3A p.Arg144Trp Uncertain significance ★ ⚠ same type
APOBEC3A p.Arg191Trp Uncertain significance ★ ⚠ same type
APOBEC3A p.Arg69His Uncertain significance ★ ⚠ same type
APOBEC3A p.Asp145Gly 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/apobec3a-p-arg74cys (accessed [today's date]).

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