Is SKI p.Met29Arg (c.86T>G) pathogenic?

SKI p.Met29Arg (c.86T>G) is classified Conflicting classifications of pathogenicity in SKI (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-09-27). AlphaMissense: ambiguous (0.4589); Ultra-rare (popmax 0.0134%, afr); Associated with Shprintzen-Goldberg syndrome.

What condition is associated with SKI p.Met29Arg (c.86T>G)?

SKI p.Met29Arg (c.86T>G) is associated with Shprintzen-Goldberg syndrome, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is SKI p.Met29Arg (c.86T>G) in the general population?

SKI p.Met29Arg (c.86T>G) is ultra-rare (popmax 0.0134%, afr) (gnomAD).

What do computational predictors say about SKI p.Met29Arg (c.86T>G)?

AlphaMissense predicts ambiguous (score 0.4589) — an in-silico prediction, not a clinical call.

SKI p.Met29Arg

c.86T>G · rs779415339 · VCV1764370

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4589 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, afr)

Conditions

Shprintzen-Goldberg syndrome

Computational evidence

Protein change
AlphaMissense	0.4589	ambiguous
REVEL	0.441	indeterminate
SaProt	LLR -3.82	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.5	GERP -2.2, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 253 bp · p 0.099 · regional, not allelic
Overall
CADD	21.7	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 0.0134% African / African-American · 9/67,088 alleles

Filtering AF 0.00699% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00515%

Overall 0.00105% 15/1,423,320 alleles · ultra-rare exomes 11/1,274,072 · genomes 4/149,248 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0134%	7,454
European (non-Finnish)	0.000553%	180,675

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.Met29Arg
Coding: c.86T>G
MANE Select: NM_003036
dbSNP: rs779415339
Type: single nucleotide variant
Location: chr1:2228852 (GRCh38)
Gene constraint: LOEUF 0.809 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.18 · 4 PDB
Residue 29: a turn

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.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
SKI p.Pro35Ser 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-met29arg (accessed [today's date]).

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