Is CROT p.Arg451Pro (c.1352G>C) pathogenic?

CROT p.Arg451Pro (c.1352G>C) is classified Uncertain significance in CROT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-25). AlphaMissense: likely pathogenic (0.9968); Very rare (popmax 0.00402%, afr).

How common is CROT p.Arg451Pro (c.1352G>C) in the general population?

CROT p.Arg451Pro (c.1352G>C) is very rare (popmax 0.00402%, afr) (gnomAD).

What do computational predictors say about CROT p.Arg451Pro (c.1352G>C)?

AlphaMissense predicts likely pathogenic (score 0.9968) — an in-silico prediction, not a clinical call.

CROT p.Arg451Pro

c.1352G>C · VCV3836494

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9968 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00402%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9968	likely pathogenic
REVEL	0.983	strongly pathogenic-leaning
SaProt	LLR -16.86	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 9.9	GERP 0.74, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 50 kb · p 0.53 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00402% African / African-American · 3/74,642 alleles

Filtering AF 0.00107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000496%

Overall 0.000807% 13/1,610,536 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00402%	24,881
European (non-Finnish)	0.000848%	117,884

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: CROT
Protein: p.Arg451Pro
Coding: c.1352G>C
MANE Select: NM_000443 · reported on NM_021151
Type: single nucleotide variant
Location: chr7:87391639 (GRCh38)

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

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/crot-p-arg451pro (accessed [today's date]).

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