Is API5 p.Leu159Arg (c.476T>G) pathogenic?

API5 p.Leu159Arg (c.476T>G) is classified Uncertain significance in API5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-03). AlphaMissense: likely pathogenic (0.9842); Very rare (popmax 0.00223%, eas).

How common is API5 p.Leu159Arg (c.476T>G) in the general population?

API5 p.Leu159Arg (c.476T>G) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about API5 p.Leu159Arg (c.476T>G)?

AlphaMissense predicts likely pathogenic (score 0.9842) — an in-silico prediction, not a clinical call.

API5 p.Leu159Arg

c.476T>G · VCV4641632

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9842 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9842	likely pathogenic
REVEL	0.589	indeterminate
SaProt	LLR -12.81	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.53	unconstrained · MANE · 11 kb · p 7.3e-13 · regional, not allelic
Overall
CADD	27.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00223% East Asian · 1/44,834 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000682% 11/1,613,576 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,834
African / African-American	0.00133%	74,932
European (non-Finnish)	0.000763%	131,095

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.Leu159Arg
Coding: c.476T>G
MANE Select: NM_001142930
Type: single nucleotide variant
Location: chr11:43322069 (GRCh38)
Gene constraint: LOEUF 0.211 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.04 · 3 PDB
Residue 159: the 'arm-like and heat-like helical repeats' region; an α-helix

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

Similar variants

API5 p.Ala402Thr Uncertain significance ★ ⚠ same type
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

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-leu159arg (accessed [today's date]).

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