Is CTSA p.Thr339Ile (c.1016C>T) pathogenic?

CTSA p.Thr339Ile (c.1016C>T) is classified Uncertain significance in CTSA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-29). AlphaMissense: likely benign (0.0862); Very rare (popmax 0.000678%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CTSA p.Thr339Ile (c.1016C>T)?

CTSA p.Thr339Ile (c.1016C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CTSA p.Thr339Ile (c.1016C>T) in the general population?

CTSA p.Thr339Ile (c.1016C>T) is very rare (popmax 0.000678%, nfe) (gnomAD).

What do computational predictors say about CTSA p.Thr339Ile (c.1016C>T)?

AlphaMissense predicts likely benign (score 0.0862) — an in-silico prediction, not a clinical call.

CTSA p.Thr339Ile

c.1016C>T · VCV3837307

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0862 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0862	likely benign
REVEL	0.162	moderately benign-leaning
SaProt	LLR -9.86	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 1.2	GERP 1.8, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 4,432 bp · p 0.0086 · regional, not allelic
Overall
CADD	16.48	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 0.000678% European (non-Finnish) · 8/1,180,036 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000547% 8/1,461,880 alleles · very rare

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: CTSA
Protein: p.Thr339Ile
Coding: c.1016C>T
MANE Select: NM_000308
Type: single nucleotide variant
Location: chr20:45895061 (GRCh38)
Gene constraint: LOEUF 0.851 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.59 · 12 PDB
Residue 339: an α-helix; a disulfide bond

Full CTSA 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

CTSA c.-17G>A Uncertain significance ★★ same condition
CTSA c.-41C>T Uncertain significance ★★ same condition
CTSA c.-6G>A Uncertain significance ★★ same condition
CTSA p.Ala150Thr Uncertain significance ★★ ⚠ same condition
CTSA p.Arg372Cys Uncertain significance ★★ ⚠ same condition
CTSA p.Gly454Val Uncertain significance ★★ ⚠ same condition
CTSA p.Gly52Ser Uncertain significance ★★ ⚠ same condition
CTSA p.Pro329Thr 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/ctsa-p-thr339ile (accessed [today's date]).

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