Is API5 p.Lys181Arg (c.542A>G) pathogenic?

API5 p.Lys181Arg (c.542A>G) is classified Uncertain significance in API5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-28). AlphaMissense: likely benign (0.1184); Very rare (popmax 0.000426%, nfe).

How common is API5 p.Lys181Arg (c.542A>G) in the general population?

API5 p.Lys181Arg (c.542A>G) is very rare (popmax 0.000426%, nfe) (gnomAD).

What do computational predictors say about API5 p.Lys181Arg (c.542A>G)?

AlphaMissense predicts likely benign (score 0.1184) — an in-silico prediction, not a clinical call.

API5 p.Lys181Arg

c.542A>G · VCV3931118

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1184 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000426%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1184	likely benign
REVEL	0.173	moderately benign-leaning
SaProt	LLR -8.38	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 1.9, phastCons 1
Regional constraint	o/e 0.53	unconstrained · MANE · 11 kb · p 7.3e-13 · regional, not allelic
Overall
CADD	29.7	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 0.000426% European (non-Finnish) · 5/1,173,556 alleles

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

Overall 0.000346% 5/1,443,820 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: API5
Protein: p.Lys181Arg
Coding: c.542A>G
MANE Select: NM_001142930
Type: single nucleotide variant
Location: chr11:43322135 (GRCh38)
Gene constraint: LOEUF 0.211 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.04 · 3 PDB
Residue 181: 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-lys181arg (accessed [today's date]).

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