Is VSIG8 p.Pro16Ser (c.46C>T) pathogenic?

VSIG8 p.Pro16Ser (c.46C>T) is classified Uncertain significance in VSIG8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-02). AlphaMissense: ambiguous (0.3747); Ultra-rare (popmax 0.02%, amr).

How common is VSIG8 p.Pro16Ser (c.46C>T) in the general population?

VSIG8 p.Pro16Ser (c.46C>T) is ultra-rare (popmax 0.02%, amr) (gnomAD).

What do computational predictors say about VSIG8 p.Pro16Ser (c.46C>T)?

AlphaMissense predicts ambiguous (score 0.3747) — an in-silico prediction, not a clinical call.

VSIG8 p.Pro16Ser

c.46C>T · VCV3468626

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3747 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3747	ambiguous
REVEL	0.157	moderately benign-leaning
SaProt	LLR -7.76	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 7,765 bp · p 0.22 · regional, not allelic
Overall
CADD	25.7	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 0.02% Admixed American · 12/59,920 alleles

Filtering AF 0.0115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00899%

Overall 0.0013% 21/1,612,902 alleles · ultra-rare exomes 9/1,460,598 · genomes 12/152,304 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.02%	4,993
Remaining individualsnot grpmax-eligible	0.00801%	12,488
African / African-American	0.004%	25,005
European (non-Finnish)	8.48e-05%	1,179,298

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: VSIG8
Protein: p.Pro16Ser
Coding: c.46C>T
MANE Select: NM_001013661
Type: single nucleotide variant
Location: chr1:159862476 (GRCh38)
Gene constraint: LOEUF 1.047 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.97

Full VSIG8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

VSIG8 p.Ala169Thr Uncertain significance ★ ⚠ same type
VSIG8 p.Ala296Thr Uncertain significance ★ ⚠ same type
VSIG8 p.Ala315Val Uncertain significance ★ ⚠ same type
VSIG8 p.Ala35Glu Uncertain significance ★ ⚠ same type
VSIG8 p.Arg127Gln Uncertain significance ★ ⚠ same type
VSIG8 p.Arg127Trp Uncertain significance ★ ⚠ same type
VSIG8 p.Arg136Gln Uncertain significance ★ ⚠ same type
VSIG8 p.Arg136Trp Uncertain significance ★ ⚠ 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/vsig8-p-pro16ser (accessed [today's date]).

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