Is API5 p.Ala402Thr (c.1204G>A) pathogenic?

API5 p.Ala402Thr (c.1204G>A) is classified Uncertain significance in API5 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-27). AlphaMissense: likely benign (0.2064); Very rare (popmax 0.00659%, sas).

How common is API5 p.Ala402Thr (c.1204G>A) in the general population?

API5 p.Ala402Thr (c.1204G>A) is very rare (popmax 0.00659%, sas) (gnomAD).

What do computational predictors say about API5 p.Ala402Thr (c.1204G>A)?

AlphaMissense predicts likely benign (score 0.2064) — an in-silico prediction, not a clinical call.

API5 p.Ala402Thr

c.1204G>A · rs771993736 · VCV2274185

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2064 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00659%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2064	likely benign
REVEL	0.16	moderately benign-leaning
SaProt	LLR -9.60	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.75 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.49	unconstrained · MANE · 19 kb · p 2.4e-21 · regional, not allelic
Overall
CADD	25.2	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 0.00659% South Asian · 6/91,068 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.000372% 6/1,613,642 alleles · very rare exomes 6/1,461,412 · genomes 0/152,230 · joint denominator

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: API5
Protein: p.Ala402Thr
Coding: c.1204G>A
MANE Select: NM_001142930
dbSNP: rs771993736
Type: single nucleotide variant
Location: chr11:43330041 (GRCh38)
Gene constraint: LOEUF 0.211 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.04 · 3 PDB
Residue 402: an α-helix

Full API5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

API5 p.Arg243Trp Uncertain significance ★ ⚠ same type
API5 p.Asn517His Uncertain significance ★ ⚠ same type
API5 p.Asp164Glu Uncertain significance ★ ⚠ same type
API5 p.Asp359His Uncertain significance ★ ⚠ same type
API5 p.Asp427His Uncertain significance ★ ⚠ same type
API5 p.Cys234Tyr Uncertain significance ★ ⚠ same type
API5 p.Glu215Gln Uncertain significance ★ ⚠ same type
API5 p.Glu329Asp 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/api5-p-ala402thr (accessed [today's date]).

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