Is SKIC3 p.Ala1237Val (c.3710C>T) pathogenic?

SKIC3 p.Ala1237Val (c.3710C>T) is classified Conflicting classifications of pathogenicity in SKIC3 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-24). AlphaMissense: likely benign (0.3104); Rare (popmax 0.217%, sas).

How common is SKIC3 p.Ala1237Val (c.3710C>T) in the general population?

SKIC3 p.Ala1237Val (c.3710C>T) is rare (popmax 0.217%, sas) (gnomAD).

What do computational predictors say about SKIC3 p.Ala1237Val (c.3710C>T)?

AlphaMissense predicts likely benign (score 0.3104) — an in-silico prediction, not a clinical call.

SKIC3 p.Ala1237Val

c.3710C>T · rs557540994 · VCV196984

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.3104 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.217%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.3104	likely benign
REVEL	0.403	indeterminate
SaProt	LLR -9.11	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 83 kb · p 0.0074 · 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 0.217% South Asian · 198/91,066 alleles

Filtering AF 0.193% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.183%

Overall 0.0157% 253/1,613,520 alleles · rare exomes 241/1,461,430 · genomes 12/152,090 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.217%	460
Middle Eastern	0.033%	3,028
Remaining individualsnot grpmax-eligible	0.0048%	20,830
East Asian	0.00447%	22,395
European (non-Finnish)	0.00381%	26,217
Admixed American	0.00167%	60,004
Finnishnot grpmax-eligible	0.00157%	63,864
African / African-American	0.00133%	74,964

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: SKIC3
Protein: p.Ala1237Val
Coding: c.3710C>T
MANE Select: NM_014639
dbSNP: rs557540994
Type: single nucleotide variant
Location: chr5:95494774 (GRCh38)
Structure: AlphaFold pLDDT 86.17 · 7 PDB
Residue 1237: an α-helix

Full SKIC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SKIC3 p.Ala1237= Likely benign ★ same residue
SKIC3 c.1221+1G>C Likely pathogenic ★★ same type
SKIC3 c.1633-2A>G Pathogenic/Likely pathogenic ★★ same type
SKIC3 c.1757+1G>A Likely pathogenic ★★ same type
SKIC3 c.2921-1G>A Pathogenic/Likely pathogenic ★★ same type
SKIC3 c.2921-2A>G Pathogenic ★★ same type
SKIC3 p.Arg1209Ter Pathogenic/Likely pathogenic ★★ same type
SKIC3 p.Arg137Ter Pathogenic/Likely pathogenic ★★ same type

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/skic3-p-ala1237val (accessed [today's date]).

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