Is SKI p.Ala204Val (c.611C>T) pathogenic?

SKI p.Ala204Val (c.611C>T) is classified Conflicting classifications of pathogenicity in SKI (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-08-21). AlphaMissense: likely benign (0.0965); Ultra-rare (popmax 0.0833%, sas); Associated with Shprintzen-Goldberg syndrome.

What condition is associated with SKI p.Ala204Val (c.611C>T)?

SKI p.Ala204Val (c.611C>T) is associated with Shprintzen-Goldberg syndrome, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is SKI p.Ala204Val (c.611C>T) in the general population?

SKI p.Ala204Val (c.611C>T) is ultra-rare (popmax 0.0833%, sas) (gnomAD).

What do computational predictors say about SKI p.Ala204Val (c.611C>T)?

AlphaMissense predicts likely benign (score 0.0965) — an in-silico prediction, not a clinical call.

SKI p.Ala204Val

c.611C>T · rs772336192 · VCV1035650

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0965 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0833%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Shprintzen-Goldberg syndrome

Computational evidence

Protein change
AlphaMissense	0.0965	likely benign
REVEL	0.304	indeterminate
SaProt	LLR -8.35	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7	GERP 1.8, phastCons 1
Regional constraint	o/e 1.29	unconstrained · MANE · 97 bp · p 0.05 · regional, not allelic
Overall
CADD	24.7	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 0.0833% South Asian · 75/90,038 alleles

Filtering AF 0.0681% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0626%

Overall 0.00518% 83/1,601,940 alleles · ultra-rare exomes 75/1,449,688 · genomes 8/152,252 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0833%	1,201
Remaining individualsnot grpmax-eligible	0.0097%	10,304
Admixed American	0.0017%	58,712
European (non-Finnish)	8.51e-05%	1,174,616

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.Ala204Val
Coding: c.611C>T
MANE Select: NM_003036
dbSNP: rs772336192
Type: single nucleotide variant
Location: chr1:2229377 (GRCh38)
Gene constraint: LOEUF 0.809 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.18 · 4 PDB

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

Disease context

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

Also linked: familial thoracic aortic aneurysm and aortic dissection

Similar variants

SKI p.Ala204= Likely benign ★ same residue
SKI p.Gly116Glu Pathogenic/Likely pathogenic ★★ same condition
SKI p.Gly117Arg Pathogenic/Likely pathogenic ★★ same condition
SKI p.Gly117Ser Pathogenic/Likely pathogenic ★★ same condition
SKI p.Gly34Cys Pathogenic ★★ ⚠ same condition
SKI p.Gly34Ser Pathogenic/Likely pathogenic ★★ ⚠ same condition
SKI p.Gly34Val Pathogenic ★★ ⚠ same condition
SKI p.Leu32Val 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/ski-p-ala204val (accessed [today's date]).

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