Is ACR p.Arg338Pro (c.1013G>C) pathogenic?

ACR p.Arg338Pro (c.1013G>C) is classified Uncertain significance in ACR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-24). AlphaMissense: likely benign (0.0731); Very rare (popmax 0.00929%, afr).

How common is ACR p.Arg338Pro (c.1013G>C) in the general population?

ACR p.Arg338Pro (c.1013G>C) is very rare (popmax 0.00929%, afr) (gnomAD).

What do computational predictors say about ACR p.Arg338Pro (c.1013G>C)?

AlphaMissense predicts likely benign (score 0.0731) — an in-silico prediction, not a clinical call.

ACR p.Arg338Pro

c.1013G>C · VCV4636918

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0731 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00929%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0731	likely benign
REVEL	0.239	benign-leaning
SaProt	LLR -5.66	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 0.17	GERP 1
Regional constraint	o/e 1.05	unconstrained · MANE · 307 bp · p 0.66 · regional, not allelic
Overall
CADD	0.717	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 0.00929% African / African-American · 5/53,806 alleles

Filtering AF 0.00366% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00293%

Overall 0.004% 57/1,423,274 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00929%	10,761
Remaining individualsnot grpmax-eligible	0.00536%	18,655
European (non-Finnish)	0.00427%	23,424
Finnishnot grpmax-eligible	0.00394%	25,368
Admixed American	0.00218%	45,908

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: ACR
Protein: p.Arg338Pro
Coding: c.1013G>C
MANE Select: NM_001097
Type: single nucleotide variant
Location: chr22:50744954 (GRCh38)
Gene constraint: LOEUF 0.943 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.10
Residue 338: a UniProt-annotated variant site (in spgf87; likely pathogenic; loss of protein expression in patient sperm); the 'disordered' region

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

Similar variants

ACR p.Arg338Gln Uncertain significance ★ ⚠ same residue
ACR p.Arg338Gly Uncertain significance ★ ⚠ same residue
ACR c.566-4A>G Benign ★★ same type
ACR p.Met296Val Benign ★★ same type
ACR p.Ala226Thr Uncertain significance ★ ⚠ same type
ACR p.Ala267Ser Uncertain significance ★ ⚠ same type
ACR p.Ala293Thr Uncertain significance ★ ⚠ same type
ACR p.Ala48Ser 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/acr-p-arg338pro (accessed [today's date]).

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