Is ACR p.Pro348Leu (c.1043C>T) pathogenic?

ACR p.Pro348Leu (c.1043C>T) is classified Uncertain significance in ACR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-04). AlphaMissense: likely benign (0.1042); Rare (popmax 0.2%, amr).

How common is ACR p.Pro348Leu (c.1043C>T) in the general population?

ACR p.Pro348Leu (c.1043C>T) is rare (popmax 0.2%, amr) (gnomAD).

What do computational predictors say about ACR p.Pro348Leu (c.1043C>T)?

AlphaMissense predicts likely benign (score 0.1042) — an in-silico prediction, not a clinical call.

ACR p.Pro348Leu

c.1043C>T · rs762995513 · VCV2213560

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1042 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.2%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1042	likely benign
REVEL	0.303	indeterminate
SaProt	LLR -10.61	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 -0.69	GERP -2.1
Regional constraint	o/e 1.05	unconstrained · MANE · 307 bp · p 0.66 · regional, not allelic
Overall
CADD	2.267	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 0.2% Admixed American · 78/39,094 alleles

Filtering AF 0.164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.151%

Overall 0.00869% 86/989,608 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.2%	501
Remaining individualsnot grpmax-eligible	0.0143%	6,995
African / African-American	0.00422%	23,684

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.Pro348Leu
Coding: c.1043C>T
MANE Select: NM_001097
dbSNP: rs762995513
Type: single nucleotide variant
Location: chr22:50744984 (GRCh38)
Gene constraint: LOEUF 0.943 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.10
Residue 348: 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-pro348leu (accessed [today's date]).

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