Is CTSD p.Ser144Trp (c.431C>G) pathogenic?

CTSD p.Ser144Trp (c.431C>G) is classified Uncertain significance in CTSD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-17). AlphaMissense: likely pathogenic (0.9299); Very rare (popmax 0.000339%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CTSD p.Ser144Trp (c.431C>G)?

CTSD p.Ser144Trp (c.431C>G) is associated with Inborn genetic diseases (ClinVar).

How common is CTSD p.Ser144Trp (c.431C>G) in the general population?

CTSD p.Ser144Trp (c.431C>G) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about CTSD p.Ser144Trp (c.431C>G)?

AlphaMissense predicts likely pathogenic (score 0.9299) — an in-silico prediction, not a clinical call.

CTSD p.Ser144Trp

c.431C>G · rs754147413 · VCV589875

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9299 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9299	likely pathogenic
REVEL	0.435	indeterminate
SaProt	LLR -14.66	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 1.5, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 10 kb · p 0.0029 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000339% European (non-Finnish) · 4/1,179,874 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00041% 6/1,461,696 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
Remaining individualsnot grpmax-eligible	0.0016%	62,498
European (non-Finnish)grpmax	0.000339%	294,969

Ashkenazi Jewish 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.Ser144Trp
Coding: c.431C>G
MANE Select: NM_001909
dbSNP: rs754147413
Type: single nucleotide variant
Location: chr11:1759009 (GRCh38)
Gene constraint: LOEUF 0.886 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.69 · 9 PDB
Residue 144: a disulfide bond; 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

Similar variants

CTSD p.Ser144Leu Uncertain significance ★★ ⚠ same residue
CTSD p.Ser144= Benign/Likely benign ★★ 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
CTSD p.Gly362Arg 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-ser144trp (accessed [today's date]).

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