Is EGLN2 p.Pro129Ser (c.385C>T) pathogenic?

EGLN2 p.Pro129Ser (c.385C>T) is classified Uncertain significance in EGLN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-26). AlphaMissense: likely benign (0.0941); Very rare (popmax 0.0022%, sas).

How common is EGLN2 p.Pro129Ser (c.385C>T) in the general population?

EGLN2 p.Pro129Ser (c.385C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about EGLN2 p.Pro129Ser (c.385C>T)?

AlphaMissense predicts likely benign (score 0.0941) — an in-silico prediction, not a clinical call.

EGLN2 p.Pro129Ser

c.385C>T · VCV4663428

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0941 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0941	likely benign
REVEL	0.04	moderately benign-leaning
SaProt	LLR -6.61	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 2.2	phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 830 bp · p 0.68 · regional, not allelic
Overall
CADD	21.4	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 0.0022% South Asian · 2/90,874 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000559% 9/1,611,122 alleles · very rare exomes 9/1,458,770 · genomes 0/152,352 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,437
Remaining individualsnot grpmax-eligible	0.0016%	62,398
European (non-Finnish)	0.000509%	196,499

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: EGLN2
Protein: p.Pro129Ser
Coding: c.385C>T
MANE Select: NM_080732
Type: single nucleotide variant
Location: chr19:40800957 (GRCh38)
Gene constraint: LOEUF 0.582 · pLI 0.67 (gnomAD)
Structure: AlphaFold pLDDT 69.05 · 1 PDB
Residue 129: the 'disordered' region

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

Similar variants

EGLN2 p.Pro129Leu Uncertain significance ★ ⚠ same residue
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

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-pro129ser (accessed [today's date]).

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