Is APIP p.Arg131Trp (c.391C>T) pathogenic?

APIP p.Arg131Trp (c.391C>T) is classified Uncertain significance in APIP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). AlphaMissense: likely benign (0.1821); Ultra-rare (popmax 0.0244%, sas).

How common is APIP p.Arg131Trp (c.391C>T) in the general population?

APIP p.Arg131Trp (c.391C>T) is ultra-rare (popmax 0.0244%, sas) (gnomAD).

What do computational predictors say about APIP p.Arg131Trp (c.391C>T)?

AlphaMissense predicts likely benign (score 0.1821) — an in-silico prediction, not a clinical call.

APIP p.Arg131Trp

c.391C>T · VCV4123301

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1821 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0244%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1821	likely benign
REVEL	0.097	moderately benign-leaning
SaProt	LLR -13.53	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 3.7	GERP 0.1, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 34 kb · p 0.0028 · regional, not allelic
Overall
CADD	25.5	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 0.0244% South Asian · 22/90,140 alleles

Filtering AF 0.0164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0139%

Overall 0.00646% 104/1,610,452 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0735%	1,361
South Asiangrpmax	0.0244%	4,097
Middle Eastern	0.0165%	6,054
East Asian	0.0134%	7,449
Remaining individualsnot grpmax-eligible	0.0128%	7,800
Admixed American	0.00335%	29,811
European (non-Finnish)	0.00144%	69,316
African / African-American	0.00134%	74,772

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg131Trp
Coding: c.391C>T
MANE Select: NM_015957
Type: single nucleotide variant
Location: chr11:34888363 (GRCh38)
Gene constraint: LOEUF 1.423 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.41 · 1 PDB
Residue 131: a β-strand

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-arg131trp (accessed [today's date]).

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