Is CTSH p.Tyr262Cys (c.785A>G) pathogenic?

CTSH p.Tyr262Cys (c.785A>G) is classified Uncertain significance in CTSH (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-21). AlphaMissense: likely pathogenic (0.9841); Absent from gnomAD v4.1.

How common is CTSH p.Tyr262Cys (c.785A>G) in the general population?

CTSH p.Tyr262Cys (c.785A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CTSH p.Tyr262Cys (c.785A>G)?

AlphaMissense predicts likely pathogenic (score 0.9841) — an in-silico prediction, not a clinical call.

CTSH p.Tyr262Cys

c.785A>G · rs2505190298 · VCV2268508

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9841 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9841	likely pathogenic · top 9% in CTSH
REVEL	0.844	moderately pathogenic-leaning
SaProt	LLR -13.44	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 7.8	GERP 2.3, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 23 kb · p 0.37 · regional, not allelic
Overall
CADD	25.6	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

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: CTSH
Protein: p.Tyr262Cys
Coding: c.785A>G
MANE Select: NM_004390
dbSNP: rs2505190298
Type: single nucleotide variant
Location: chr15:78925355 (GRCh38)
Gene constraint: LOEUF 1.267 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.30 · 2 PDB
Residue 262: a disulfide bond; a β-strand

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

Similar variants

CTSH p.Ala23Thr Benign ★★ same type
CTSH p.Gly11= Benign ★★ same type
CTSH p.Thr48= Benign ★★ same type
CTSH p.Ala10Val Uncertain significance ★ ⚠ same type
CTSH p.Ala149Ser Uncertain significance ★ ⚠ same type
CTSH p.Ala155Thr Uncertain significance ★ ⚠ same type
CTSH p.Ala165Val Uncertain significance ★ ⚠ same type
CTSH p.Ala23Val 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/ctsh-p-tyr262cys (accessed [today's date]).

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