Is EGLN2 p.Pro331Ser (c.991C>T) pathogenic?

EGLN2 p.Pro331Ser (c.991C>T) is classified Uncertain significance in EGLN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-12). AlphaMissense: likely pathogenic (0.9934); Absent from gnomAD v4.1.

How common is EGLN2 p.Pro331Ser (c.991C>T) in the general population?

EGLN2 p.Pro331Ser (c.991C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EGLN2 p.Pro331Ser (c.991C>T)?

AlphaMissense predicts likely pathogenic (score 0.9934) — an in-silico prediction, not a clinical call.

EGLN2 p.Pro331Ser

c.991C>T · rs2516008649 · VCV3229027

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9934 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9934	likely pathogenic
REVEL	0.424	indeterminate
SaProt	LLR -12.91	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 6,457 bp · p 2.3e-07 · regional, not allelic
Overall
CADD	29.3	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

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: EGLN2
Protein: p.Pro331Ser
Coding: c.991C>T
MANE Select: NM_080732
dbSNP: rs2516008649
Type: single nucleotide variant
Location: chr19:40807165 (GRCh38)
Gene constraint: LOEUF 0.582 · pLI 0.67 (gnomAD)
Structure: AlphaFold pLDDT 69.05 · 1 PDB
Residue 331: the fe2og dioxygenase domain

Full EGLN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EGLN2 p.Ala137Thr Uncertain significance ★★ ⚠ same type
EGLN2 p.Arg236Cys Uncertain significance ★★ ⚠ same type
EGLN2 p.Arg306Cys Uncertain significance ★★ ⚠ same type
EGLN2 c.1100+23C>A Benign ★★ same type
EGLN2 c.844-141G>A Benign ★★ same type
EGLN2 c.844-199G>A Benign ★★ same type
EGLN2 c.963+33G>C Benign ★★ same type
EGLN2 c.-116G>A 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/egln2-p-pro331ser (accessed [today's date]).

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