Is CTSD p.Met326Lys (c.977T>A) pathogenic?

CTSD p.Met326Lys (c.977T>A) is classified Uncertain significance in CTSD (ClinVar, Single submitter, 1 submitter; last evaluated 2020-03-13). AlphaMissense: ambiguous (0.5538); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with CTSD p.Met326Lys (c.977T>A)?

CTSD p.Met326Lys (c.977T>A) is associated with Inborn genetic diseases (ClinVar).

How common is CTSD p.Met326Lys (c.977T>A) in the general population?

CTSD p.Met326Lys (c.977T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CTSD p.Met326Lys (c.977T>A)?

AlphaMissense predicts ambiguous (score 0.5538) — an in-silico prediction, not a clinical call.

CTSD p.Met326Lys

c.977T>A · rs1565018786 · VCV1768172

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5538 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5538	ambiguous
REVEL	0.269	benign-leaning
SaProt	LLR -8.18	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.99 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 10 kb · p 0.0029 · regional, not allelic
Overall
CADD	25.9	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CTSD
Protein: p.Met326Lys
Coding: c.977T>A
MANE Select: NM_001909
dbSNP: rs1565018786
Type: single nucleotide variant
Location: chr11:1753897 (GRCh38)
Gene constraint: LOEUF 0.886 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.69 · 9 PDB
Residue 326: the peptidase a1 domain; a β-strand

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

Similar variants

CTSD p.Met326Thr Uncertain significance ★ ⚠ same residue
CTSD p.Met326Ile Uncertain significance ★ ⚠ same residue
CTSD p.Met326Val Uncertain significance ★ ⚠ same residue
CTSD p.Ala116Thr Uncertain significance ★★ ⚠ same condition
CTSD p.Ala18Pro Uncertain significance ★★ ⚠ same condition
CTSD p.Arg205His Uncertain significance ★★ ⚠ same condition
CTSD p.Arg392His Uncertain significance ★★ ⚠ same condition
CTSD p.Asp387Asn 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-met326lys (accessed [today's date]).

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