Is CROT p.Phe103Ser (c.308T>C) pathogenic?

CROT p.Phe103Ser (c.308T>C) is classified Uncertain significance in CROT (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-21). AlphaMissense: likely pathogenic (0.9291); Very rare (popmax 0.000847%, nfe).

How common is CROT p.Phe103Ser (c.308T>C) in the general population?

CROT p.Phe103Ser (c.308T>C) is very rare (popmax 0.000847%, nfe) (gnomAD).

What do computational predictors say about CROT p.Phe103Ser (c.308T>C)?

AlphaMissense predicts likely pathogenic (score 0.9291) — an in-silico prediction, not a clinical call.

CROT p.Phe103Ser

c.308T>C · rs1447446261 · VCV2329208

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9291 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000847%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9291	likely pathogenic · top 10% in CROT
REVEL	0.897	moderately pathogenic-leaning
SaProt	LLR -7.22	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 50 kb · p 0.53 · regional, not allelic
Overall
CADD	27.1	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 0.000847% European (non-Finnish) · 10/1,179,978 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.00062% 10/1,614,028 alleles · very rare exomes 10/1,461,756 · genomes 0/152,272 · joint denominator

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.Phe103Ser
Coding: c.308T>C
MANE Select: NM_021151
dbSNP: rs1447446261
Type: single nucleotide variant
Location: chr7:87361457 (GRCh38)
Gene constraint: LOEUF 1.003 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.22

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

Similar variants

CROT c.116-1631C>T Uncertain significance ★ same type
CROT c.116-1651G>A Uncertain significance ★ same type
CROT c.116-1663C>A Uncertain significance ★ same type
CROT c.116-1686C>G Uncertain significance ★ same type
CROT p.Ala104Val Uncertain significance ★ ⚠ same type
CROT p.Arg12Gln Uncertain significance ★ ⚠ same type
CROT p.Arg160Gln Uncertain significance ★ ⚠ same type
CROT p.Arg389Gly 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/crot-p-phe103ser (accessed [today's date]).

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