Is CROT p.Ser473Pro (c.1417T>C) pathogenic?

CROT p.Ser473Pro (c.1417T>C) is classified Uncertain significance in CROT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-09). AlphaMissense: ambiguous (0.4047); Very rare (popmax 0.00672%, afr).

How common is CROT p.Ser473Pro (c.1417T>C) in the general population?

CROT p.Ser473Pro (c.1417T>C) is very rare (popmax 0.00672%, afr) (gnomAD).

What do computational predictors say about CROT p.Ser473Pro (c.1417T>C)?

AlphaMissense predicts ambiguous (score 0.4047) — an in-silico prediction, not a clinical call.

CROT p.Ser473Pro

c.1417T>C · VCV4656789

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4047 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00672%, afr)

Computational evidence

Protein change
AlphaMissense	0.4047	ambiguous
REVEL	0.345	indeterminate
SaProt	LLR -12.88	damaging
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 1.2	GERP -1.1, phastCons 0.015
Regional constraint	o/e 0.98	unconstrained · MANE · 50 kb · p 0.53 · regional, not allelic
Overall
CADD	17.21	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 0.00672% African / African-American · 5/74,430 alleles

Filtering AF 0.00256% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00162%

Overall 0.000311% 5/1,606,942 alleles · very rare

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.Ser473Pro
Coding: c.1417T>C
MANE Select: NM_000443 · reported on NM_021151
Type: single nucleotide variant
Location: chr7:87391704 (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-ser473pro (accessed [today's date]).

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