Is ACR p.Pro310Leu (c.929C>T) pathogenic?

ACR p.Pro310Leu (c.929C>T) is classified Uncertain significance in ACR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). AlphaMissense: likely benign (0.0747); Very rare (popmax 0.00783%, nfe).

How common is ACR p.Pro310Leu (c.929C>T) in the general population?

ACR p.Pro310Leu (c.929C>T) is very rare (popmax 0.00783%, nfe) (gnomAD).

What do computational predictors say about ACR p.Pro310Leu (c.929C>T)?

AlphaMissense predicts likely benign (score 0.0747) — an in-silico prediction, not a clinical call.

ACR p.Pro310Leu

c.929C>T · VCV4218034

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0747 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00783%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0747	likely benign
REVEL	0.277	benign-leaning
SaProt	LLR -9.11	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 0.23	GERP -2.3, phastCons 0.006
Regional constraint	o/e 0.49	unconstrained · MANE · 125 bp · p 8e-05 · regional, not allelic
Overall
CADD	1.201	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 0.00783% European (non-Finnish) · 92/1,174,486 alleles

Filtering AF 0.00651% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00603%

Overall 0.00632% 101/1,598,572 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00783%	12,766
African / African-American	0.00563%	17,766
Remaining individualsnot grpmax-eligible	0.00484%	20,681
Admixed American	0.0017%	58,844
South Asian	0.00112%	89,546

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.Pro310Leu
Coding: c.929C>T
MANE Select: NM_001097
Type: single nucleotide variant
Location: chr22:50744870 (GRCh38)
Gene constraint: LOEUF 0.943 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.10
Residue 310: 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 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
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-pro310leu (accessed [today's date]).

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