Is SKIC2 p.Pro44Ser (c.130C>T) pathogenic?

SKIC2 p.Pro44Ser (c.130C>T) is classified Uncertain significance in SKIC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-07). AlphaMissense: ambiguous (0.4488); Very rare (popmax 0.0022%, sas); Associated with Inborn genetic diseases.

What condition is associated with SKIC2 p.Pro44Ser (c.130C>T)?

SKIC2 p.Pro44Ser (c.130C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SKIC2 p.Pro44Ser (c.130C>T) in the general population?

SKIC2 p.Pro44Ser (c.130C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about SKIC2 p.Pro44Ser (c.130C>T)?

AlphaMissense predicts ambiguous (score 0.4488) — an in-silico prediction, not a clinical call.

SKIC2 p.Pro44Ser

c.130C>T · VCV4630947

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4488 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4488	ambiguous
REVEL	0.109	moderately benign-leaning
SaProt	LLR -6.47	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.35 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 11 kb · p 3.8e-08 · regional, not allelic
Overall
CADD	23.7	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 0.0022% South Asian · 2/91,068 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000124% 2/1,612,212 alleles · very rare exomes 2/1,459,914 · genomes 0/152,298 · joint denominator

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: SKIC2
Protein: p.Pro44Ser
Coding: c.130C>T
MANE Select: NM_006929
Type: single nucleotide variant
Location: chr6:31960013 (GRCh38)
Structure: AlphaFold pLDDT 81.32 · 11 PDB

Full SKIC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SKIC2 p.Pro44= Conflicting classifications of pathogenicity ★ same residue
SKIC2 p.Ala289Thr Uncertain significance ★★ ⚠ same condition
SKIC2 p.Ala538Gly Uncertain significance ★★ ⚠ same condition
SKIC2 p.Ala565Val Uncertain significance ★★ ⚠ same condition
SKIC2 p.Arg1001Gln Uncertain significance ★★ ⚠ same condition
SKIC2 p.Arg1003Trp Uncertain significance ★★ ⚠ same condition
SKIC2 p.Arg1019Cys Uncertain significance ★★ ⚠ same condition
SKIC2 p.Arg1041Cys 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/skic2-p-pro44ser (accessed [today's date]).

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