Is CTSC p.Val249Phe (c.745G>T) pathogenic?

CTSC p.Val249Phe (c.745G>T) is classified Likely pathogenic in CTSC (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-22). AlphaMissense: likely pathogenic (0.765); Absent from gnomAD v4.1; Associated with Haim-Munk syndrome.

What condition is associated with CTSC p.Val249Phe (c.745G>T)?

CTSC p.Val249Phe (c.745G>T) is associated with Haim-Munk syndrome (ClinVar).

How common is CTSC p.Val249Phe (c.745G>T) in the general population?

CTSC p.Val249Phe (c.745G>T) is absent from gnomAD v4.1 (gnomAD).

How is Haim-Munk syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CTSC p.Val249Phe (c.745G>T)?

AlphaMissense predicts likely pathogenic (score 0.765) — an in-silico prediction, not a clinical call.

CTSC p.Val249Phe

c.745G>T · VCV3377550

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.765 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Haim-Munk syndrome

Computational evidence

Protein change
AlphaMissense	0.765	likely pathogenic ✓ concordant with ClinVar
REVEL	0.896	moderately pathogenic-leaning
SaProt	LLR -14.71	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.4, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 44 kb · p 0.26 · regional, not allelic
Overall
CADD	29.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CTSC
Protein: p.Val249Phe
Coding: c.745G>T
MANE Select: NM_001814
Type: single nucleotide variant
Location: chr11:88300542 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.64 · 18 PDB
Residue 249: a UniProt-annotated variant site (in pls); an α-helix

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

Disease context

Haim-Munk syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Haim-Munk syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

CTSC c.319-1G>A Pathogenic ★★ same condition
CTSC c.757+1G>T Likely pathogenic ★★ same condition
CTSC c.-55C>A Pathogenic ★★ same condition
CTSC p.Arg210Ter Pathogenic ★★ same condition
CTSC p.Arg250Ter Pathogenic/Likely pathogenic ★★ same condition
CTSC p.Arg272His Pathogenic/Likely pathogenic ★★ ⚠ same condition
CTSC p.Arg272Pro Pathogenic/Likely pathogenic ★★ same condition
CTSC p.Arg339Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition

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/ctsc-p-val249phe (accessed [today's date]).

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