Is CTSH p.Gly159Arg (c.475G>A) pathogenic?

CTSH p.Gly159Arg (c.475G>A) is classified Uncertain significance in CTSH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-25). AlphaMissense: likely benign (0.2866); Ultra-rare (popmax 0.0111%, eas).

How common is CTSH p.Gly159Arg (c.475G>A) in the general population?

CTSH p.Gly159Arg (c.475G>A) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

What do computational predictors say about CTSH p.Gly159Arg (c.475G>A)?

AlphaMissense predicts likely benign (score 0.2866) — an in-silico prediction, not a clinical call.

CTSH p.Gly159Arg

c.475G>A · rs758377577 · VCV2515040

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2866 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2866	likely benign
REVEL	0.303	indeterminate
SaProt	LLR -11.22	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 23 kb · p 0.37 · regional, not allelic
Overall
CADD	25.8	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 0.0111% East Asian · 5/44,894 alleles

Filtering AF 0.00434% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.00173% 28/1,613,938 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.016%	6,249
East Asiangrpmax	0.0111%	8,979
African / African-American	0.004%	24,971
South Asian	0.00329%	30,361
Admixed American	0.00167%	59,994
European (non-Finnish)	0.000508%	196,657

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Gly159Arg
Coding: c.475G>A
MANE Select: NM_004390
dbSNP: rs758377577
Type: single nucleotide variant
Location: chr15:78932389 (GRCh38)
Gene constraint: LOEUF 1.267 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.30 · 2 PDB
Residue 159: a disulfide bond

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-gly159arg (accessed [today's date]).

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