Is API5 p.Glu215Gln (c.643G>C) pathogenic?

API5 p.Glu215Gln (c.643G>C) is classified Uncertain significance in API5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-15). AlphaMissense: ambiguous (0.47); Very rare (popmax 0.00329%, sas).

How common is API5 p.Glu215Gln (c.643G>C) in the general population?

API5 p.Glu215Gln (c.643G>C) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about API5 p.Glu215Gln (c.643G>C)?

AlphaMissense predicts ambiguous (score 0.47) — an in-silico prediction, not a clinical call.

API5 p.Glu215Gln

c.643G>C · VCV4833651

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.47 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.47	ambiguous
REVEL	0.256	benign-leaning
SaProt	LLR -7.00	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 1.18	unconstrained · MANE · 78 bp · p 0.31 · regional, not allelic
Overall
CADD	22.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00329% South Asian · 3/91,088 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000372% 6/1,614,062 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,363
Remaining individualsnot grpmax-eligible	0.0016%	62,488
European (non-Finnish)	0.000169%	590,009

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.Glu215Gln
Coding: c.643G>C
MANE Select: NM_001142930
Type: single nucleotide variant
Location: chr11:43323529 (GRCh38)
Gene constraint: LOEUF 0.211 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.04 · 3 PDB
Residue 215: 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.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-glu215gln (accessed [today's date]).

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