Is CTNS p.Ala122Thr (c.364G>A) pathogenic?

CTNS p.Ala122Thr (c.364G>A) is classified Conflicting classifications of pathogenicity in CTNS (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0633); Rare (popmax 0.546%, sas); Associated with Inborn genetic diseases.

What condition is associated with CTNS p.Ala122Thr (c.364G>A)?

CTNS p.Ala122Thr (c.364G>A) is associated with Inborn genetic diseases, ocular cystinosis, juvenile nephropathic cystinosis (ClinVar).

How common is CTNS p.Ala122Thr (c.364G>A) in the general population?

CTNS p.Ala122Thr (c.364G>A) is rare (popmax 0.546%, sas) (gnomAD).

What do computational predictors say about CTNS p.Ala122Thr (c.364G>A)?

AlphaMissense predicts likely benign (score 0.0633) — an in-silico prediction, not a clinical call.

CTNS p.Ala122Thr

c.364G>A · rs187396540 · VCV712938

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0633 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.546%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0633	likely benign
REVEL	0.299	indeterminate
SaProt	LLR -6.35	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP -6.1	GERP -3.7
Regional constraint	o/e 0.96	unconstrained · MANE · 20 kb · p 0.4 · regional, not allelic
Overall
CADD	0.01	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 0.546% South Asian · 497/91,076 alleles

Filtering AF 0.506% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.49%

Overall 0.0387% 624/1,614,166 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.546%	183
East Asian	0.167%	598
Middle Eastern	0.0495%	2,021
Remaining individualsnot grpmax-eligible	0.0416%	2,404
African / African-American	0.00266%	37,525
European (non-Finnish)	0.00178%	56,192

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: CTNS
Protein: p.Ala122Thr
Coding: c.364G>A
MANE Select: NM_004937
dbSNP: rs187396540
Type: single nucleotide variant
Location: chr17:3655255 (GRCh38)
Gene constraint: LOEUF 0.754 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.27 · 6 PDB
Residue 122: an α-helix

Full CTNS 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: ocular cystinosis juvenile nephropathic cystinosis cystinosis nephropathic cystinosis

Similar variants

CTNS p.Ala122Val Uncertain significance ★ ⚠ same residue
CTNS p.Ala122= Likely benign ★ same residue
CTNS c.140+1G>C Likely pathogenic ★★ same condition
CTNS c.140+1G>T Pathogenic/Likely pathogenic ★★ same condition
CTNS c.140+2T>C Pathogenic/Likely pathogenic ★★ same condition
CTNS c.141-1G>A Pathogenic/Likely pathogenic ★★ same condition
CTNS c.141-24T>C Pathogenic ★★ same condition
CTNS c.225+3A>T Pathogenic/Likely pathogenic ★★ 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/ctns-p-ala122thr (accessed [today's date]).

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