Is CTSH p.Arg317Cys (c.949C>T) pathogenic?

CTSH p.Arg317Cys (c.949C>T) is classified Likely benign in CTSH (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-11-09). AlphaMissense: likely pathogenic (0.8255); Rare (popmax 0.382%, amr); Associated with CTSH-related disorder.

What condition is associated with CTSH p.Arg317Cys (c.949C>T)?

CTSH p.Arg317Cys (c.949C>T) is associated with CTSH-related disorder (ClinVar).

How common is CTSH p.Arg317Cys (c.949C>T) in the general population?

CTSH p.Arg317Cys (c.949C>T) is rare (popmax 0.382%, amr) (gnomAD).

What do computational predictors say about CTSH p.Arg317Cys (c.949C>T)?

AlphaMissense predicts likely pathogenic (score 0.8255) — an in-silico prediction, not a clinical call.

CTSH p.Arg317Cys

c.949C>T · rs11558397 · VCV3041827

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8255 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.382%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CTSH-related disorder

Computational evidence

Protein change
AlphaMissense	0.8255	likely pathogenic
REVEL	0.793	moderately pathogenic-leaning
SaProt	LLR -17.47	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 9.6	GERP 2.4, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 23 kb · p 0.37 · regional, not allelic
Overall
CADD	33.0	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 0.382% Admixed American · 210/55,012 alleles

Filtering AF 0.339% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.323%

Overall 0.0273% 431/1,580,696 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.382%	262
East Asian	0.336%	298
African / African-American	0.0456%	2,192
Remaining individualsnot grpmax-eligible	0.0343%	2,914
European (non-Finnish)	0.00172%	58,195

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: CTSH
Protein: p.Arg317Cys
Coding: c.949C>T
MANE Select: NM_004390
dbSNP: rs11558397
Type: single nucleotide variant
Location: chr15:78922189 (GRCh38)
Gene constraint: LOEUF 1.267 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.30 · 2 PDB
Residue 317: a disulfide bond

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

Disease context

CTSH-related disorder

Similar variants

CTSH p.Asn66= Likely benign same condition
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

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-arg317cys (accessed [today's date]).

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