Is ELN p.Pro667Ser (c.1999C>T) pathogenic?

ELN p.Pro667Ser (c.1999C>T) is classified Conflicting classifications of pathogenicity in ELN (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.0426); Low-frequency (popmax 1.58%, mid); Associated with supravalvular aortic stenosis.

What condition is associated with ELN p.Pro667Ser (c.1999C>T)?

ELN p.Pro667Ser (c.1999C>T) is associated with supravalvular aortic stenosis, cutis laxa, autosomal dominant 1, Williams syndrome (ClinVar).

How common is ELN p.Pro667Ser (c.1999C>T) in the general population?

ELN p.Pro667Ser (c.1999C>T) is low-frequency (popmax 1.58%, mid) (gnomAD).

What do computational predictors say about ELN p.Pro667Ser (c.1999C>T)?

AlphaMissense predicts likely benign (score 0.0426) — an in-silico prediction, not a clinical call.

ELN p.Pro667Ser

c.1999C>T · rs142316834 · VCV213166

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.0426 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.58%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

supravalvular aortic stenosis

Computational evidence

Protein change
AlphaMissense	0.0426	likely benign
REVEL	0.024	moderately benign-leaning
SaProt	LLR -2.51	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.034	GERP 4.6, phastCons 0.87
Regional constraint	o/e 0.91	unconstrained · MANE · 41 kb · p 0.005 · regional, not allelic
Overall
CADD	12.21	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 P729S vs ClinVar P667S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.58% Middle Eastern · 96/6,062 alleles

Filtering AF 1.33% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.23%

Overall 0.0349% 563/1,613,806 alleles · low-frequency exomes 501/1,461,834 · genomes 62/151,972 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	1.58%	63
Remaining individualsnot grpmax-eligible	0.08%	1,250
Ashkenazi Jewishnot grpmax-eligible	0.0574%	1,741
South Asian	0.0527%	1,897
African / African-American	0.044%	2,270
Admixed American	0.0433%	2,307
European (non-Finnish)	0.0248%	4,027

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.Pro667Ser
Coding: c.1999C>T
MANE Select: NM_000501
dbSNP: rs142316834
Type: single nucleotide variant
Location: chr7:74065699 (GRCh38)
Gene constraint: LOEUF 0.696 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 36.20

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

Disease context

supravalvular aortic stenosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cutis laxa, autosomal dominant 1 Williams syndrome autosomal dominant cutis laxa

Similar variants

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
ELN c.82+1G>A Pathogenic/Likely pathogenic ★★ same condition
ELN c.889+1G>A Pathogenic/Likely 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-pro667ser (accessed [today's date]).

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