Is APIP p.Arg14Trp (c.40C>T) pathogenic?

APIP p.Arg14Trp (c.40C>T) is classified Uncertain significance in APIP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-26). AlphaMissense: likely benign (0.1432); Ultra-rare (popmax 0.0107%, nfe).

How common is APIP p.Arg14Trp (c.40C>T) in the general population?

APIP p.Arg14Trp (c.40C>T) is ultra-rare (popmax 0.0107%, nfe) (gnomAD).

What do computational predictors say about APIP p.Arg14Trp (c.40C>T)?

AlphaMissense predicts likely benign (score 0.1432) — an in-silico prediction, not a clinical call.

APIP p.Arg14Trp

c.40C>T · VCV3883659

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1432 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1432	likely benign
REVEL	0.037	moderately benign-leaning
SaProt	LLR -9.57	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 0.48	GERP 0.03
Regional constraint	o/e 0.83	unconstrained · MANE · 34 kb · p 0.0028 · regional, not allelic
Overall
CADD	14.75	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 0.0107% European (non-Finnish) · 126/1,179,450 alleles

Filtering AF 0.00911% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00855%

Overall 0.00813% 131/1,612,124 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0107%	9,361
African / African-American	0.00534%	18,724
Remaining individualsnot grpmax-eligible	0.0016%	62,366

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.Arg14Trp
Coding: c.40C>T
MANE Select: NM_015957
Type: single nucleotide variant
Location: chr11:34916245 (GRCh38)
Gene constraint: LOEUF 1.423 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.41 · 1 PDB

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-arg14trp (accessed [today's date]).

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