Is EPN2 p.Ser237Pro (c.709T>C) pathogenic?

EPN2 p.Ser237Pro (c.709T>C) is classified Uncertain significance in EPN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-30). AlphaMissense: likely benign (0.0635); Ultra-rare (popmax 0.0601%, afr).

How common is EPN2 p.Ser237Pro (c.709T>C) in the general population?

EPN2 p.Ser237Pro (c.709T>C) is ultra-rare (popmax 0.0601%, afr) (gnomAD).

What do computational predictors say about EPN2 p.Ser237Pro (c.709T>C)?

AlphaMissense predicts likely benign (score 0.0635) — an in-silico prediction, not a clinical call.

EPN2 p.Ser237Pro

c.709T>C · VCV3509512

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0635 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0601%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0635	likely benign
REVEL	0.082	moderately benign-leaning
SaProt	LLR -6.05	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 1.1	GERP 0.46, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 29 kb · p 2.8e-08 · regional, not allelic
Overall
CADD	18.31	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 0.0601% African / African-American · 45/74,850 alleles

Filtering AF 0.0461% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0412%

Overall 0.00323% 52/1,608,270 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0601%	1,663
Middle Eastern	0.0413%	2,424
Remaining individualsnot grpmax-eligible	0.00483%	20,706
Admixed American	0.00168%	59,642
South Asian	0.00111%	89,958

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: EPN2
Protein: p.Ser237Pro
Coding: c.709T>C
MANE Select: NM_014964
Type: single nucleotide variant
Location: chr17:19285733 (GRCh38)
Gene constraint: LOEUF 0.804 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.50

Full EPN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EPN2 p.Ala102Thr Uncertain significance ★ ⚠ same type
EPN2 p.Ala253Gly Uncertain significance ★ ⚠ same type
EPN2 p.Ala254Asp Uncertain significance ★ same type
EPN2 p.Ala347Thr Uncertain significance ★ ⚠ same type
EPN2 p.Ala347Val Uncertain significance ★ ⚠ same type
EPN2 p.Ala412Val Uncertain significance ★ ⚠ same type
EPN2 p.Ala428Thr Uncertain significance ★ ⚠ same type
EPN2 p.Ala428Val 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/epn2-p-ser237pro (accessed [today's date]).

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