Is EAPP p.Arg239Gln (c.716G>A) pathogenic?

EAPP p.Arg239Gln (c.716G>A) is classified Benign in EAPP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-04-19). AlphaMissense: likely benign (0.054); Common (popmax 17.1%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about EAPP p.Arg239Gln (c.716G>A)?

AlphaMissense predicts likely benign (score 0.054) — an in-silico prediction, not a clinical call.

EAPP p.Arg239Gln

Q: How common is EAPP p.Arg239Gln (c.716G>A) in the general population?

EAPP p.Arg239Gln (c.716G>A) is common (popmax 17.1%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.716G>A · rs17856037 · VCV1291338

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.054 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 17.1%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.054	likely benign
REVEL	0.015	strongly benign-leaning
SaProt	LLR -5.55	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 -3.8	GERP -4.2
Regional constraint	o/e 0.98	unconstrained · MANE · 23 kb · p 0.76 · regional, not allelic
Overall
CADD	8.478	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 17.1% African / African-American · 12,816/74,970 alleles

Filtering AF 16.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 16.7%

Overall 3.06% 49,334/1,614,004 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	17.1%	6
Middle Eastern	3.32%	30
Remaining individualsnot grpmax-eligible	3.11%	32
European (non-Finnish)	2.57%	39
Admixed American	2.51%	40
Ashkenazi Jewishnot grpmax-eligible	1.9%	53
South Asian	1.21%	82
Finnishnot grpmax-eligible	1.12%	89
East Asian	0.47%	213

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: EAPP
Protein: p.Arg239Gln
Coding: c.716G>A
MANE Select: NM_018453
dbSNP: rs17856037
Type: single nucleotide variant
Location: chr14:34516452 (GRCh38)
Gene constraint: LOEUF 1.441 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.38

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

Similar variants

EAPP p.Ala183Val Uncertain significance ★ ⚠ same type
EAPP p.Ala267Val Uncertain significance ★ ⚠ same type
EAPP p.Ala282Thr Uncertain significance ★ ⚠ same type
EAPP p.Ala95Ser Uncertain significance ★ ⚠ same type
EAPP p.Arg156Ser Uncertain significance ★ ⚠ same type
EAPP p.Arg229Ser Uncertain significance ★ ⚠ same type
EAPP p.Arg236Lys Uncertain significance ★ ⚠ same type
EAPP p.Arg236Ser 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/eapp-p-arg239gln (accessed [today's date]).

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