Is SKI p.Val114Ala (c.341T>C) pathogenic?

SKI p.Val114Ala (c.341T>C) is classified Uncertain significance in SKI (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-25). AlphaMissense: likely pathogenic (0.5897); Very rare (popmax 0.000424%, nfe); Associated with familial thoracic aortic aneurysm and aortic dissection.

What condition is associated with SKI p.Val114Ala (c.341T>C)?

SKI p.Val114Ala (c.341T>C) is associated with familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is SKI p.Val114Ala (c.341T>C) in the general population?

SKI p.Val114Ala (c.341T>C) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about SKI p.Val114Ala (c.341T>C)?

AlphaMissense predicts likely pathogenic (score 0.5897) — an in-silico prediction, not a clinical call.

SKI p.Val114Ala

Q: How is Familial thoracic aortic aneurysm and aortic dissection inherited?

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

c.341T>C · VCV4635535

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5897 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial thoracic aortic aneurysm and aortic dissection

Computational evidence

Protein change
AlphaMissense	0.5897	likely pathogenic
REVEL	0.69	pathogenic-leaning
SaProt	LLR -7.70	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP -2.3, phastCons 1
Regional constraint	o/e 0.53	unconstrained · MANE · 289 bp · p 4.9e-08 · regional, not allelic
Overall
CADD	28.1	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,179,822 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000373% 6/1,610,068 alleles · very rare exomes 6/1,458,008 · genomes 0/152,060 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,444
European (non-Finnish)grpmax	0.000424%	235,964

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: SKI
Protein: p.Val114Ala
Coding: c.341T>C
MANE Select: NM_003036
Type: single nucleotide variant
Location: chr1:2229107 (GRCh38)
Gene constraint: LOEUF 0.809 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.18 · 4 PDB
Residue 114: a β-strand

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

Disease context

familial thoracic aortic aneurysm and aortic dissection — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial thoracic aortic aneurysm and aortic dissection (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

SKI p.Val114Met Uncertain significance ★★ same residue
SKI p.Val114Leu Uncertain significance ★ ⚠ same residue
SKI p.Val114= Likely benign ★ same residue
SKI p.Pro35Ser Pathogenic ★★ ⚠ same condition
SKI p.Thr180Met Pathogenic/Likely pathogenic ★★ same condition
SKI c.1999-3C>T Uncertain significance ★★ same condition
SKI p.Ala208Pro Uncertain significance ★★ ⚠ same condition
SKI p.Ala208Val Uncertain significance ★★ ⚠ 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/ski-p-val114ala (accessed [today's date]).

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