Is CTSD p.Arg205His (c.614G>A) pathogenic?

CTSD p.Arg205His (c.614G>A) is classified Uncertain significance in CTSD (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-08-31). AlphaMissense: likely benign (0.1098); Ultra-rare (popmax 0.036%, afr); Associated with Inborn genetic diseases.

What condition is associated with CTSD p.Arg205His (c.614G>A)?

CTSD p.Arg205His (c.614G>A) is associated with Inborn genetic diseases, neuronal ceroid lipofuscinosis (ClinVar).

How common is CTSD p.Arg205His (c.614G>A) in the general population?

CTSD p.Arg205His (c.614G>A) is ultra-rare (popmax 0.036%, afr) (gnomAD).

What do computational predictors say about CTSD p.Arg205His (c.614G>A)?

AlphaMissense predicts likely benign (score 0.1098) — an in-silico prediction, not a clinical call.

CTSD p.Arg205His

c.614G>A · rs371522391 · VCV862579

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1098 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.036%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1098	likely benign
REVEL	0.075	moderately benign-leaning
SaProt	LLR -6.27	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 -0.18	GERP -3.6
Regional constraint	o/e 0.87	unconstrained · MANE · 10 kb · p 0.0029 · regional, not allelic
Overall
CADD	20.5	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 0.036% African / African-American · 27/74,944 alleles

Filtering AF 0.0254% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0219%

Overall 0.00242% 39/1,614,014 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.036%	2,776
Admixed American	0.005%	20,003
Remaining individualsnot grpmax-eligible	0.0048%	20,828
South Asian	0.0022%	45,543
European (non-Finnish)	0.000339%	295,009

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.Arg205His
Coding: c.614G>A
MANE Select: NM_001909
dbSNP: rs371522391
Type: single nucleotide variant
Location: chr11:1757414 (GRCh38)
Gene constraint: LOEUF 0.886 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.69 · 9 PDB
Residue 205: 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

Similar variants

CTSD p.Arg205Cys Uncertain significance ★ ⚠ same residue
CTSD p.Arg205Gly Uncertain significance ★ ⚠ 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-arg205his (accessed [today's date]).

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