Is CLTCL1 p.Phe252Ser (c.755T>C) pathogenic?

CLTCL1 p.Phe252Ser (c.755T>C) is classified Uncertain significance in CLTCL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-27). AlphaMissense: likely pathogenic (0.7656); Very rare (popmax 0.00167%, amr).

How common is CLTCL1 p.Phe252Ser (c.755T>C) in the general population?

CLTCL1 p.Phe252Ser (c.755T>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CLTCL1 p.Phe252Ser (c.755T>C)?

AlphaMissense predicts likely pathogenic (score 0.7656) — an in-silico prediction, not a clinical call.

CLTCL1 p.Phe252Ser

c.755T>C · VCV3834224

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7656 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7656	likely pathogenic · top 5% in CLTCL1
REVEL	0.536	indeterminate
SaProt	LLR -13.87	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 0.8, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 111 kb · p 0.00057 · regional, not allelic
Overall
CADD	23.3	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 0.00167% Admixed American · 1/60,014 alleles

Overall 6.84e-05% 1/1,461,712 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: CLTCL1
Protein: p.Phe252Ser
Coding: c.755T>C
MANE Select: NM_007098
Type: single nucleotide variant
Location: chr22:19239315 (GRCh38)
Gene constraint: LOEUF 0.993 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.53
Residue 252: the 'wd40-like repeat 5' region; the 'globular terminal domain' region

Full CLTCL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLTCL1 p.Arg1226Cys Uncertain significance ★★ ⚠ same type
CLTCL1 p.Gln1113Lys Uncertain significance ★★ ⚠ same type
CLTCL1 p.Gln1142Arg Uncertain significance ★★ ⚠ same type
CLTCL1 p.Glu1212Lys Uncertain significance ★★ ⚠ same type
CLTCL1 p.Gly464Arg Uncertain significance ★★ ⚠ same type
CLTCL1 p.Ser1061Gly Uncertain significance ★★ ⚠ same type
CLTCL1 p.Ser707Gly Uncertain significance ★★ ⚠ same type
CLTCL1 p.Val948Gly 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/cltcl1-p-phe252ser (accessed [today's date]).

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