Is CTSD p.Val277Met (c.829G>A) pathogenic?

CTSD p.Val277Met (c.829G>A) is classified Uncertain significance in CTSD (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-31). AlphaMissense: likely benign (0.2132); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

What condition is associated with CTSD p.Val277Met (c.829G>A)?

CTSD p.Val277Met (c.829G>A) is associated with Inborn genetic diseases, neuronal ceroid lipofuscinosis (ClinVar).

How common is CTSD p.Val277Met (c.829G>A) in the general population?

CTSD p.Val277Met (c.829G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CTSD p.Val277Met (c.829G>A)?

AlphaMissense predicts likely benign (score 0.2132) — an in-silico prediction, not a clinical call.

CTSD p.Val277Met

c.829G>A · rs372319807 · VCV840289

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2132 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2132	likely benign
REVEL	0.24	benign-leaning
SaProt	LLR -7.78	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 -0.9
Regional constraint	o/e 0.87	unconstrained · MANE · 10 kb · p 0.0029 · regional, not allelic
Overall
CADD	2.693	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 0.00223% East Asian · 1/44,840 alleles

Overall 0.000249% 4/1,608,386 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00321%	31,172
East Asiangrpmax	0.00223%	44,840
South Asian	0.0011%	90,948

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: CTSD
Protein: p.Val277Met
Coding: c.829G>A
MANE Select: NM_001909
dbSNP: rs372319807
Type: single nucleotide variant
Location: chr11:1754137 (GRCh38)
Gene constraint: LOEUF 0.886 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.69 · 9 PDB
Residue 277: a β-strand; the peptidase a1 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: neuronal ceroid lipofuscinosis

Similar variants

CTSD p.Val277Leu Uncertain significance ★ ⚠ same residue
CTSD p.Val277= Likely benign ★ same residue
CTSD c.228+1G>A Likely pathogenic ★★ same condition
CTSD p.Glu82Ter Pathogenic/Likely pathogenic ★★ same condition
CTSD c.828-3C>A Uncertain significance ★★ same condition
CTSD p.Ala10Ser Uncertain significance ★★ ⚠ same condition
CTSD p.Ala116Thr Uncertain significance ★★ ⚠ same condition
CTSD p.Ala18Pro Uncertain significance ★★ ⚠ same condition

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/ctsd-p-val277met (accessed [today's date]).

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