Is ACR p.Arg200Pro (c.599G>C) pathogenic?

ACR p.Arg200Pro (c.599G>C) is classified Uncertain significance in ACR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-28). AlphaMissense: likely benign (0.2883); Ultra-rare (popmax 0.0293%, afr).

How common is ACR p.Arg200Pro (c.599G>C) in the general population?

ACR p.Arg200Pro (c.599G>C) is ultra-rare (popmax 0.0293%, afr) (gnomAD).

What do computational predictors say about ACR p.Arg200Pro (c.599G>C)?

AlphaMissense predicts likely benign (score 0.2883) — an in-silico prediction, not a clinical call.

ACR p.Arg200Pro

c.599G>C · rs371232787 · VCV2287811

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2883 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0293%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2883	likely benign
REVEL	0.341	indeterminate
SaProt	LLR -6.81	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.19	GERP -2
Regional constraint	o/e 0.84	unconstrained · MANE · 6,534 bp · p 0.0026 · regional, not allelic
Overall
CADD	15.18	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 0.0293% African / African-American · 22/74,976 alleles

Filtering AF 0.0198% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0167%

Overall 0.00174% 28/1,613,764 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0293%	3,408
Remaining individualsnot grpmax-eligible	0.0048%	20,827
Admixed American	0.00333%	29,999
European (non-Finnish)	8.48e-05%	1,179,780

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.Arg200Pro
Coding: c.599G>C
MANE Select: NM_001097
dbSNP: rs371232787
Type: single nucleotide variant
Location: chr22:50744094 (GRCh38)
Gene constraint: LOEUF 0.943 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.10
Residue 200: a disulfide bond; a UniProt-annotated variant site (in spgf87; likely pathogenic; loss of protein expression in patient sperm); the peptidase s1 domain

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

Similar variants

ACR p.Arg200His 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
ACR p.Arg156Cys 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-arg200pro (accessed [today's date]).

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