Is CROT p.Trp306Arg (c.916T>C) pathogenic?

CROT p.Trp306Arg (c.916T>C) is classified Uncertain significance in CROT (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-04). AlphaMissense: likely pathogenic (0.9974); Ultra-rare (popmax 0.0352%, sas).

How common is CROT p.Trp306Arg (c.916T>C) in the general population?

CROT p.Trp306Arg (c.916T>C) is ultra-rare (popmax 0.0352%, sas) (gnomAD).

What do computational predictors say about CROT p.Trp306Arg (c.916T>C)?

AlphaMissense predicts likely pathogenic (score 0.9974) — an in-silico prediction, not a clinical call.

CROT p.Trp306Arg

c.916T>C · VCV3497266

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9974 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0352%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9974	likely pathogenic
REVEL	0.915	moderately pathogenic-leaning
SaProt	LLR -13.24	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 6.2	GERP 0.74, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 50 kb · p 0.53 · regional, not allelic
Overall
CADD	28.2	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 0.0352% South Asian · 32/90,988 alleles

Filtering AF 0.0256% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0223%

Overall 0.00558% 90/1,611,886 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0352%	2,843
European (non-Finnish)	0.00467%	21,426
Remaining individualsnot grpmax-eligible	0.00321%	31,194
Finnishnot grpmax-eligible	0.00156%	63,970

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.Trp306Arg
Coding: c.916T>C
MANE Select: NM_000443 · reported on NM_021151
Type: single nucleotide variant
Location: chr7:87377388 (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-trp306arg (accessed [today's date]).

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