Is ACR p.Met296Val (c.886A>G) pathogenic?

ACR p.Met296Val (c.886A>G) is classified Benign in ACR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2016-03-28). AlphaMissense: likely benign (0.0857); Common (popmax 83%, eas) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about ACR p.Met296Val (c.886A>G)?

AlphaMissense predicts likely benign (score 0.0857) — an in-silico prediction, not a clinical call.

ACR p.Met296Val

Q: How common is ACR p.Met296Val (c.886A>G) in the general population?

ACR p.Met296Val (c.886A>G) is common (popmax 83%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.886A>G · rs5771002 · VCV402336

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0857 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 83%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0857	likely benign
REVEL	0.163	moderately benign-leaning
SaProt	LLR -4.91	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 -0.2	GERP -2.2
Regional constraint	o/e 0.49	unconstrained · MANE · 125 bp · p 8e-05 · regional, not allelic
Overall
CADD	0.336	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 83% East Asian · 36,418/43,890 alleles

Filtering AF 82.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 82%

Overall 68.3% 1,092,782/1,600,480 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	83%	1
South Asian	80.6%	1
Amishnot grpmax-eligible	76.3%	1
Ashkenazi Jewishnot grpmax-eligible	73.9%	1
Admixed American	71.9%	1
Finnishnot grpmax-eligible	71.1%	1
Middle Eastern	68.8%	1
Remaining individualsnot grpmax-eligible	68.5%	1
African / African-American	66.5%	2
European (non-Finnish)	66.4%	2

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.Met296Val
Coding: c.886A>G
MANE Select: NM_001097
dbSNP: rs5771002
Type: single nucleotide variant
Location: chr22:50744827 (GRCh38)
Gene constraint: LOEUF 0.943 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.10
Residue 296: a UniProt-annotated variant site (in spgf87; likely pathogenic; loss of protein expression in patient sperm)

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

Similar variants

ACR p.Met296Ile Uncertain significance ★ ⚠ same residue
ACR c.566-4A>G 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
ACR p.Arg156Cys Uncertain significance ★ ⚠ same type
ACR p.Arg156His 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-met296val (accessed [today's date]).

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