Is APEH p.Arg306Trp (c.916C>T) pathogenic?

APEH p.Arg306Trp (c.916C>T) is classified Uncertain significance in APEH (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-05). AlphaMissense: likely pathogenic (0.6505); Very rare (popmax 0.00666%, afr).

How common is APEH p.Arg306Trp (c.916C>T) in the general population?

APEH p.Arg306Trp (c.916C>T) is very rare (popmax 0.00666%, afr) (gnomAD).

What do computational predictors say about APEH p.Arg306Trp (c.916C>T)?

AlphaMissense predicts likely pathogenic (score 0.6505) — an in-silico prediction, not a clinical call.

APEH p.Arg306Trp

c.916C>T · rs752238584 · VCV2609517

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6505 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00666%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6505	likely pathogenic
REVEL	0.434	indeterminate
SaProt	LLR -16.09	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.90 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6	GERP 2.6, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 8,937 bp · p 0.011 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00666% African / African-American · 5/75,058 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.00211% 34/1,614,198 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00666%	15,012
East Asian	0.00223%	44,890
European (non-Finnish)	0.0022%	45,386
Remaining individualsnot grpmax-eligible	0.0016%	62,508
South Asian	0.0011%	91,086

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.Arg306Trp
Coding: c.916C>T
MANE Select: NM_001640
dbSNP: rs752238584
Type: single nucleotide variant
Location: chr3:49676941 (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.Arg313Leu Uncertain significance ★ ⚠ same type
APEH p.Arg383Cys Uncertain significance ★ ⚠ same type
APEH p.Arg538His Uncertain significance ★ ⚠ same type
APEH p.Arg65His 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-arg306trp (accessed [today's date]).

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