Is APEH p.Gln478Pro (c.1433A>C) pathogenic?

APEH p.Gln478Pro (c.1433A>C) is classified Uncertain significance in APEH (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-05). AlphaMissense: likely benign (0.101); Very rare (popmax 8.62e-05%, nfe).

How common is APEH p.Gln478Pro (c.1433A>C) in the general population?

APEH p.Gln478Pro (c.1433A>C) is very rare (popmax 8.62e-05%, nfe) (gnomAD).

What do computational predictors say about APEH p.Gln478Pro (c.1433A>C)?

AlphaMissense predicts likely benign (score 0.101) — an in-silico prediction, not a clinical call.

APEH p.Gln478Pro

c.1433A>C · rs535978549 · VCV2253163

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.101 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.62e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.101	likely benign
REVEL	0.175	moderately benign-leaning
SaProt	LLR -8.46	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>G here scores Δ0.79 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.1	GERP 2.3, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 8,937 bp · p 0.011 · regional, not allelic
Overall
CADD	22.3	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 8.62e-05% European (non-Finnish) · 1/1,160,292 alleles

Overall 0.000656% 1/152,342 alleles · very rare

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: APEH
Protein: p.Gln478Pro
Coding: c.1433A>C
MANE Select: NM_001640
dbSNP: rs535978549
Type: single nucleotide variant
Location: chr3:49681234 (GRCh38)
Gene constraint: LOEUF 0.87 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.58

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

Similar variants

APEH p.Arg107Cys Uncertain significance ★ ⚠ same type
APEH p.Arg128Gly Uncertain significance ★ ⚠ same type
APEH p.Arg278Cys Uncertain significance ★ ⚠ same type
APEH p.Arg278His Uncertain significance ★ ⚠ same type
APEH p.Arg306Trp Uncertain significance ★ ⚠ same type
APEH p.Arg313Leu Uncertain significance ★ ⚠ same type
APEH p.Arg383Cys Uncertain significance ★ ⚠ same type
APEH p.Arg538His Uncertain significance ★ ⚠ 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/apeh-p-gln478pro (accessed [today's date]).

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