Is CUTC p.Ser249Pro (c.745T>C) pathogenic?

CUTC p.Ser249Pro (c.745T>C) is classified Uncertain significance in CUTC (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-08). AlphaMissense: likely benign (0.0934); Very rare (popmax 8.48e-05%, nfe).

How common is CUTC p.Ser249Pro (c.745T>C) in the general population?

CUTC p.Ser249Pro (c.745T>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about CUTC p.Ser249Pro (c.745T>C)?

AlphaMissense predicts likely benign (score 0.0934) — an in-silico prediction, not a clinical call.

CUTC p.Ser249Pro

c.745T>C · rs2492781715 · VCV2265933

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0934 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0934	likely benign
REVEL	0.091	moderately benign-leaning
SaProt	LLR -5.64	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
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 0.92	unconstrained · MANE · 23 kb · p 0.12 · regional, not allelic
Overall
CADD	17.61	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 8.48e-05% European (non-Finnish) · 1/1,179,796 alleles

Overall 6.84e-05% 1/1,461,522 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: CUTC
Protein: p.Ser249Pro
Coding: c.745T>C
MANE Select: NM_015960
dbSNP: rs2492781715
Type: single nucleotide variant
Location: chr10:99755662 (GRCh38)
Gene constraint: LOEUF 1.218 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.70 · 1 PDB

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

Similar variants

COX15 c.-435C>T Benign ★★ same type
COX15 c.-472T>C Uncertain significance ★ same type
CUTC p.Ala13Pro Uncertain significance ★ ⚠ same type
CUTC p.Ala268Thr Uncertain significance ★ ⚠ same type
CUTC p.Ala46Asp Uncertain significance ★ ⚠ same type
CUTC p.Arg104Cys Uncertain significance ★ ⚠ same type
CUTC p.Arg104His Uncertain significance ★ ⚠ same type
CUTC p.Arg12Gly 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/cutc-p-ser249pro (accessed [today's date]).

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