Is ELN p.Ala637Thr (c.1909G>A) pathogenic?

ELN p.Ala637Thr (c.1909G>A) is classified Conflicting classifications of pathogenicity in ELN (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-07-07). AlphaMissense: likely benign (0.2396); Rare (popmax 0.223%, mid); Associated with Williams syndrome.

What condition is associated with ELN p.Ala637Thr (c.1909G>A)?

ELN p.Ala637Thr (c.1909G>A) is associated with Williams syndrome, cutis laxa, autosomal dominant 1, supravalvular aortic stenosis (ClinVar).

How common is ELN p.Ala637Thr (c.1909G>A) in the general population?

ELN p.Ala637Thr (c.1909G>A) is rare (popmax 0.223%, mid) (gnomAD).

What do computational predictors say about ELN p.Ala637Thr (c.1909G>A)?

AlphaMissense predicts likely benign (score 0.2396) — an in-silico prediction, not a clinical call.

ELN p.Ala637Thr

c.1909G>A · rs536177240 · VCV360660

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.2396 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.223%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Williams syndrome

Computational evidence

Protein change
AlphaMissense	0.2396	likely benign
REVEL	0.054	moderately benign-leaning
SaProt	LLR -11.41	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do 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	25.9	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 A699T vs ClinVar A637T) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.223% Middle Eastern · 11/4,922 alleles

Filtering AF 0.125% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0969%

Overall 0.00905% 140/1,547,070 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.223%	447
European (non-Finnish)	0.00959%	10,432
Remaining individualsnot grpmax-eligible	0.00833%	12,004
African / African-American	0.0082%	12,195
Finnishnot grpmax-eligible	0.00718%	13,921
Admixed American	0.00392%	25,511
East Asian	0.00244%	40,974
South Asian	0.00119%	84,196

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.Ala637Thr
Coding: c.1909G>A
MANE Select: NM_000501
dbSNP: rs536177240
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

Disease context

Williams syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cutis laxa, autosomal dominant 1 supravalvular aortic stenosis familial thoracic aortic aneurysm and aortic dissection

Similar variants

ELN p.Ala637Ser Uncertain significance ★★ ⚠ same residue
ELN p.Ala637Pro Uncertain significance ★ same residue
ELN c.377-2A>G Pathogenic/Likely pathogenic ★★ same condition
ELN c.643+1G>C Likely pathogenic ★★ same condition
ELN c.686-2A>G Likely pathogenic ★★ same condition
ELN c.800-1G>A Pathogenic/Likely pathogenic ★★ same condition
ELN c.800-2A>G Pathogenic ★★ same condition
ELN c.800-3C>G Pathogenic ★★ same condition

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-ala637thr (accessed [today's date]).

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