Is CTSD p.Arg309His (c.926G>A) pathogenic?

CTSD p.Arg309His (c.926G>A) is classified Conflicting classifications of pathogenicity in CTSD (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.1304); Ultra-rare (popmax 0.038%, eas); Associated with Inborn genetic diseases.

What condition is associated with CTSD p.Arg309His (c.926G>A)?

CTSD p.Arg309His (c.926G>A) is associated with Inborn genetic diseases, neuronal ceroid lipofuscinosis 10, neuronal ceroid lipofuscinosis (ClinVar).

How common is CTSD p.Arg309His (c.926G>A) in the general population?

CTSD p.Arg309His (c.926G>A) is ultra-rare (popmax 0.038%, eas) (gnomAD).

What do computational predictors say about CTSD p.Arg309His (c.926G>A)?

AlphaMissense predicts likely benign (score 0.1304) — an in-silico prediction, not a clinical call.

CTSD p.Arg309His

c.926G>A · rs374540411 · VCV205360

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1304 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.038%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1304	likely benign
REVEL	0.089	moderately benign-leaning
SaProt	LLR -7.75	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 -0.28
Regional constraint	o/e 0.87	unconstrained · MANE · 10 kb · p 0.0029 · regional, not allelic
Overall
CADD	19.93	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 0.038% East Asian · 17/44,788 alleles

Filtering AF 0.0241% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0205%

Overall 0.0077% 124/1,610,514 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.038%	2,635
South Asian	0.033%	3,030
Remaining individualsnot grpmax-eligible	0.0289%	3,466
African / African-American	0.008%	12,501
European (non-Finnish)	0.00441%	22,678
Admixed American	0.00167%	59,848

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.Arg309His
Coding: c.926G>A
MANE Select: NM_001909
dbSNP: rs374540411
Type: single nucleotide variant
Location: chr11:1754040 (GRCh38)
Gene constraint: LOEUF 0.886 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.69 · 9 PDB
Residue 309: an α-helix; 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 10 neuronal ceroid lipofuscinosis

Similar variants

CTSD p.Arg309= 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 c.*210C>G 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-arg309his (accessed [today's date]).

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