Is APIP p.Val222Ile (c.664G>A) pathogenic?

APIP p.Val222Ile (c.664G>A) is classified Likely benign in APIP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-10). AlphaMissense: likely benign (0.1081); Ultra-rare (popmax 0.0165%, mid).

How common is APIP p.Val222Ile (c.664G>A) in the general population?

APIP p.Val222Ile (c.664G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about APIP p.Val222Ile (c.664G>A)?

AlphaMissense predicts likely benign (score 0.1081) — an in-silico prediction, not a clinical call.

APIP p.Val222Ile

c.664G>A · VCV3306557

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1081 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1081	likely benign
REVEL	0.128	moderately benign-leaning
SaProt	LLR -10.48	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.61	GERP -2.2, phastCons 0.093
Regional constraint	o/e 0.83	unconstrained · MANE · 34 kb · p 0.0028 · regional, not allelic
Overall
CADD	14.52	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00728% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00525%

Overall 0.00392% 63/1,608,494 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
East Asian	0.0157%	6,387
South Asian	0.0122%	8,223
Remaining individualsnot grpmax-eligible	0.00803%	12,453
Admixed American	0.00671%	14,907
African / African-American	0.00536%	18,671
European (non-Finnish)	0.00264%	37,946

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.Val222Ile
Coding: c.664G>A
MANE Select: NM_015957
Type: single nucleotide variant
Location: chr11:34882782 (GRCh38)
Gene constraint: LOEUF 1.423 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.41 · 1 PDB
Residue 222: 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-val222ile (accessed [today's date]).

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