Is ELN p.Ala637Pro (c.1909G>C) pathogenic?

ELN p.Ala637Pro (c.1909G>C) is classified Uncertain significance in ELN (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-17). AlphaMissense: likely pathogenic (0.7525); Very rare (popmax 7.17e-05%).

How common is ELN p.Ala637Pro (c.1909G>C) in the general population?

ELN p.Ala637Pro (c.1909G>C) is very rare (popmax 7.17e-05%) (gnomAD).

What do computational predictors say about ELN p.Ala637Pro (c.1909G>C)?

AlphaMissense predicts likely pathogenic (score 0.7525) — an in-silico prediction, not a clinical call.

ELN p.Ala637Pro

c.1909G>C · VCV4896252

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7525 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 7.17e-05%)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7525	likely pathogenic
REVEL	0.204	benign-leaning
SaProt	LLR -11.46	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8	GERP 5, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 41 kb · p 0.005 · regional, not allelic
Overall
CADD	22.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A699P vs ClinVar A637P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 7.17e-05%

Overall 7.17e-05% 1/1,394,826 alleles · very rare

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: ELN
Protein: p.Ala637Pro
Coding: c.1909G>C
MANE Select: NM_000501
Type: single nucleotide variant
Location: chr7:74063360 (GRCh38)
Gene constraint: LOEUF 0.696 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 36.20
Residue 637: the 'disordered' region

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

Similar variants

ELN p.Ala637Ser Uncertain significance ★★ ⚠ same residue
ELN p.Ala637Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
ELN c.134-1G>A Likely pathogenic ★★ same type
ELN c.377-2A>G Pathogenic/Likely pathogenic ★★ same type
ELN c.643+1G>A Pathogenic/Likely pathogenic ★★ same type
ELN c.643+1G>C Likely pathogenic ★★ same type
ELN c.686-2A>G Likely pathogenic ★★ same type
ELN c.800-1G>A Pathogenic/Likely pathogenic ★★ 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/eln-p-ala637pro (accessed [today's date]).

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