Is APIP p.Arg67Gln (c.200G>A) pathogenic?

APIP p.Arg67Gln (c.200G>A) is classified Uncertain significance in APIP (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-14). AlphaMissense: ambiguous (0.4139); Ultra-rare (popmax 0.0868%, afr).

How common is APIP p.Arg67Gln (c.200G>A) in the general population?

APIP p.Arg67Gln (c.200G>A) is ultra-rare (popmax 0.0868%, afr) (gnomAD).

What do computational predictors say about APIP p.Arg67Gln (c.200G>A)?

AlphaMissense predicts ambiguous (score 0.4139) — an in-silico prediction, not a clinical call.

APIP p.Arg67Gln

c.200G>A · rs201392083 · VCV2374586

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4139 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0868%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4139	ambiguous
REVEL	0.147	moderately benign-leaning
SaProt	LLR -7.41	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 4.1	GERP 2.1, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 34 kb · p 0.0028 · regional, not allelic
Overall
CADD	26.9	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 0.0868% African / African-American · 65/74,844 alleles

Filtering AF 0.0699% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0637%

Overall 0.00715% 115/1,609,306 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0868%	1,151
Admixed American	0.0302%	3,310
South Asian	0.0199%	5,023
East Asian	0.00895%	11,171
Remaining individualsnot grpmax-eligible	0.00803%	12,453
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,480
European (non-Finnish)	0.00034%	294,422

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: APIP
Protein: p.Arg67Gln
Coding: c.200G>A
MANE Select: NM_015957
dbSNP: rs201392083
Type: single nucleotide variant
Location: chr11:34890511 (GRCh38)
Gene constraint: LOEUF 1.423 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.41 · 1 PDB
Residue 67: an α-helix

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

Similar variants

PDHX c.-302A>G Benign ★★ same type
PDHX c.-319G>A Benign ★★ same type
PDHX c.-390G>A Benign ★★ ⚠ same type
PDHX c.-505G>A Benign ★★ same type
PDHX c.-506T>C Benign ★★ same type
PDHX c.-717G>C Benign ★★ same type
PDHX c.-787G>A Benign ★★ same type
PDHX c.-840C>T Benign ★★ 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/apip-p-arg67gln (accessed [today's date]).

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