Is ELN p.Ala127= (c.381G>A) pathogenic?

ELN p.Ala127= (c.381G>A) is classified Likely benign in ELN (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-18). Ultra-rare (popmax 0.0614%, afr); Associated with cutis laxa, autosomal dominant 1.

What condition is associated with ELN p.Ala127= (c.381G>A)?

ELN p.Ala127= (c.381G>A) is associated with cutis laxa, autosomal dominant 1, supravalvular aortic stenosis, Williams syndrome (ClinVar).

How common is ELN p.Ala127= (c.381G>A) in the general population?

ELN p.Ala127= (c.381G>A) is ultra-rare (popmax 0.0614%, afr) (gnomAD).

How is Autosomal dominant cutis laxa inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

ELN p.Ala127=

c.381G>A · rs148216123 · VCV1114743

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0614%, afr)

Conditions

cutis laxa, autosomal dominant 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.64	acceptor gain · deltas
Pangolin	Δ0.27	gain · loss 0.05 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -20	GERP -13
Overall
CADD	15.53	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0614% African / African-American · 46/74,902 alleles

Filtering AF 0.0472% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0423%

Overall 0.00614% 99/1,613,316 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0614%	1,628
Middle Eastern	0.0493%	2,027
Remaining individualsnot grpmax-eligible	0.0144%	6,940
South Asian	0.0044%	22,744
Finnishnot grpmax-eligible	0.00313%	31,983
European (non-Finnish)	0.00288%	34,699
Admixed American	0.00167%	59,794

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.Ala127=
Coding: c.381G>A
MANE Select: NM_000501
dbSNP: rs148216123
Type: single nucleotide variant
Location: chr7:74043122 (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

cutis laxa, autosomal dominant 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: supravalvular aortic stenosis Williams syndrome

For Autosomal dominant cutis laxa (Orphanet):

Inheritance: Autosomal dominant
Onset: Infancy, Neonatal

Similar variants

ELN p.Ala127Val 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
ELN c.82+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-ala127 (accessed [today's date]).

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