Is CTSD p.Ala77= (c.231C>T) pathogenic?

CTSD p.Ala77= (c.231C>T) is classified Benign in CTSD (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-02-04). Common (popmax 12.5%, mid) — too common for a highly-penetrant pathogenic allele; Associated with neuronal ceroid lipofuscinosis.

What condition is associated with CTSD p.Ala77= (c.231C>T)?

CTSD p.Ala77= (c.231C>T) is associated with neuronal ceroid lipofuscinosis, neuronal ceroid lipofuscinosis 10 (ClinVar).

CTSD p.Ala77=

Q: How common is CTSD p.Ala77= (c.231C>T) in the general population?

CTSD p.Ala77= (c.231C>T) is common (popmax 12.5%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.231C>T · rs2230067 · VCV128875

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

gnomAD v4.1

Common

common (popmax 12.5%, mid) — too common for a highly-penetrant pathogenic allele

Conditions

neuronal ceroid lipofuscinosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.32 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.9	GERP -3.7, phastCons 1
Overall
CADD	14.72	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 12.5% Middle Eastern · 754/6,038 alleles

Filtering AF 11.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 11.5%

Overall 7.81% 125,861/1,612,446 alleles · common

Ancestry group	Frequency	1 in
Middle Easterngrpmax	12.5%	8
South Asian	9.48%	11
Ashkenazi Jewishnot grpmax-eligible	8.84%	11
European (non-Finnish)	8.4%	12
Remaining individualsnot grpmax-eligible	8.08%	12
Admixed American	5.35%	19
Finnishnot grpmax-eligible	5.05%	20
African / African-American	2.94%	34
East Asian	2.5%	40
Amishnot grpmax-eligible	2.3%	43

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.Ala77=
Coding: c.231C>T
MANE Select: NM_001909
dbSNP: rs2230067
Type: single nucleotide variant
Location: chr11:1759637 (GRCh38)
Gene constraint: LOEUF 0.886 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.69 · 9 PDB
Residue 77: a turn

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

Disease context

neuronal ceroid lipofuscinosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: neuronal ceroid lipofuscinosis 10

Similar variants

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.Ala18Pro Uncertain significance ★★ ⚠ same condition
CTSD p.Ala18Thr Uncertain significance ★★ ⚠ same condition
CTSD p.Ala239Val 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-ala77 (accessed [today's date]).

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