Is ACR p.Pro366Leu (c.1097C>T) pathogenic?

ACR p.Pro366Leu (c.1097C>T) is classified Uncertain significance in ACR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-12). AlphaMissense: likely benign (0.1006); Ultra-rare (popmax 0.0207%, nfe).

How common is ACR p.Pro366Leu (c.1097C>T) in the general population?

ACR p.Pro366Leu (c.1097C>T) is ultra-rare (popmax 0.0207%, nfe) (gnomAD).

What do computational predictors say about ACR p.Pro366Leu (c.1097C>T)?

AlphaMissense predicts likely benign (score 0.1006) — an in-silico prediction, not a clinical call.

ACR p.Pro366Leu

c.1097C>T · VCV4218114

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1006 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0207%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1006	likely benign
REVEL	0.324	indeterminate
SaProt	LLR -11.45	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.34	GERP -1.6, phastCons 0.01
Regional constraint	o/e 1.05	unconstrained · MANE · 307 bp · p 0.66 · regional, not allelic
Overall
CADD	6.49	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 0.0207% European (non-Finnish) · 83/400,492 alleles

Filtering AF 0.0171% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0158%

Overall 0.014% 87/621,814 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0207%	4,825
Remaining individualsnot grpmax-eligible	0.0101%	9,915
Finnishnot grpmax-eligible	0.00306%	32,676

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.Pro366Leu
Coding: c.1097C>T
MANE Select: NM_001097
Type: single nucleotide variant
Location: chr22:50745038 (GRCh38)
Gene constraint: LOEUF 0.943 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.10
Residue 366: 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-pro366leu (accessed [today's date]).

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