Is CTSH p.Met260Val (c.778A>G) pathogenic?

CTSH p.Met260Val (c.778A>G) is classified Uncertain significance in CTSH (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-28). AlphaMissense: likely benign (0.1454); Ultra-rare (popmax 0.0227%, afr).

How common is CTSH p.Met260Val (c.778A>G) in the general population?

CTSH p.Met260Val (c.778A>G) is ultra-rare (popmax 0.0227%, afr) (gnomAD).

What do computational predictors say about CTSH p.Met260Val (c.778A>G)?

AlphaMissense predicts likely benign (score 0.1454) — an in-silico prediction, not a clinical call.

CTSH p.Met260Val

c.778A>G · rs138844057 · VCV3078779

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1454 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0227%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1454	likely benign
REVEL	0.26	benign-leaning
SaProt	LLR -7.25	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.2	GERP -4, phastCons 0.42
Regional constraint	o/e 0.96	unconstrained · MANE · 23 kb · p 0.37 · regional, not allelic
Overall
CADD	6.95	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.0227% African / African-American · 17/75,026 alleles

Filtering AF 0.0144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0118%

Overall 0.00112% 18/1,613,316 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0227%	4,413
European (non-Finnish)	8.48e-05%	1,179,298

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.Met260Val
Coding: c.778A>G
MANE Select: NM_004390
dbSNP: rs138844057
Type: single nucleotide variant
Location: chr15:78925362 (GRCh38)
Gene constraint: LOEUF 1.267 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.30 · 2 PDB
Residue 260: a disulfide bond; an α-helix

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-met260val (accessed [today's date]).

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