Is CTSH p.Gly304Ser (c.910G>A) pathogenic?

CTSH p.Gly304Ser (c.910G>A) is classified Uncertain significance in CTSH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-10). AlphaMissense: ambiguous (0.4884); Very rare (popmax 0.00224%, eas).

How common is CTSH p.Gly304Ser (c.910G>A) in the general population?

CTSH p.Gly304Ser (c.910G>A) is very rare (popmax 0.00224%, eas) (gnomAD).

What do computational predictors say about CTSH p.Gly304Ser (c.910G>A)?

AlphaMissense predicts ambiguous (score 0.4884) — an in-silico prediction, not a clinical call.

CTSH p.Gly304Ser

c.910G>A · VCV4008172

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4884 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Computational evidence

Protein change
AlphaMissense	0.4884	ambiguous
REVEL	0.534	indeterminate
SaProt	LLR -9.80	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2.1, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 23 kb · p 0.37 · regional, not allelic
Overall
CADD	26.1	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 0.00224% East Asian · 1/44,726 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000479% 7/1,460,108 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00224%	44,726
European (non-Finnish)	0.000509%	196,571

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.Gly304Ser
Coding: c.910G>A
MANE Select: NM_004390
Type: single nucleotide variant
Location: chr15:78923015 (GRCh38)
Gene constraint: LOEUF 1.267 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.30 · 2 PDB
Residue 304: 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-gly304ser (accessed [today's date]).

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