Is APIP p.Phe35Leu (c.105T>G) pathogenic?

APIP p.Phe35Leu (c.105T>G) is classified Uncertain significance in APIP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-22). AlphaMissense: likely pathogenic (0.9633); Absent from gnomAD v4.1.

How common is APIP p.Phe35Leu (c.105T>G) in the general population?

APIP p.Phe35Leu (c.105T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about APIP p.Phe35Leu (c.105T>G)?

AlphaMissense predicts likely pathogenic (score 0.9633) — an in-silico prediction, not a clinical call.

APIP p.Phe35Leu

c.105T>G · VCV4123311

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9633 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9633	likely pathogenic
REVEL	0.187	benign-leaning
SaProt	LLR -11.77	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>G here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.8	GERP -2.4, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 34 kb · p 0.0028 · regional, not allelic
Overall
CADD	21.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: APIP
Protein: p.Phe35Leu
Coding: c.105T>G
MANE Select: NM_015957
Type: single nucleotide variant
Location: chr11:34895063 (GRCh38)
Gene constraint: LOEUF 1.423 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.41 · 1 PDB
Residue 35: 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-phe35leu (accessed [today's date]).

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