Is CAB39 p.Thr40Ser (c.118A>T) pathogenic?

CAB39 p.Thr40Ser (c.118A>T) is classified Uncertain significance in CAB39 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-12). AlphaMissense: likely benign (0.0721); Very rare (popmax 0.000425%, nfe).

How common is CAB39 p.Thr40Ser (c.118A>T) in the general population?

CAB39 p.Thr40Ser (c.118A>T) is very rare (popmax 0.000425%, nfe) (gnomAD).

What do computational predictors say about CAB39 p.Thr40Ser (c.118A>T)?

AlphaMissense predicts likely benign (score 0.0721) — an in-silico prediction, not a clinical call.

CAB39 p.Thr40Ser

c.118A>T · VCV4217574

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0721 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000425%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0721	likely benign
REVEL	0.095	moderately benign-leaning
SaProt	LLR -3.53	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 11	GERP 0.21, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 59 kb · p 6e-11 · regional, not allelic
Overall
CADD	18.19	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 0.000425% European (non-Finnish) · 5/1,175,702 alleles

Filtering AF 0.000125% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.1e-05%

Overall 0.000313% 5/1,599,348 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: CAB39
Protein: p.Thr40Ser
Coding: c.118A>T
MANE Select: NM_016289
Type: single nucleotide variant
Location: chr2:230790875 (GRCh38)
Gene constraint: LOEUF 0.693 · pLI 0.67 (gnomAD)
Structure: AlphaFold pLDDT 94.77 · 10 PDB
Residue 40: an α-helix

Full CAB39 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CAB39 p.Asp239Glu Uncertain significance ★ ⚠ same type
CAB39 p.Gln69Pro Uncertain significance ★ ⚠ same type
CAB39 p.Ile110Thr Uncertain significance ★ ⚠ same type
CAB39 p.Ile303Met Uncertain significance ★ ⚠ same type
CAB39 p.Leu296Phe Uncertain significance ★ ⚠ same type
CAB39 p.Lys10Arg Uncertain significance ★ ⚠ same type
CAB39 p.Met50Val Uncertain significance ★ ⚠ same type
CAB39 p.Phe185Tyr Uncertain significance ★ ⚠ same type

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/cab39-p-thr40ser (accessed [today's date]).

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