Is HS6ST2 p.Val8Phe (c.22G>T) pathogenic?

HS6ST2 p.Val8Phe (c.22G>T) is classified Uncertain significance in HS6ST2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-11). AlphaMissense: likely benign (0.0868); No allele count reported in gnomAD v4.1 (AN 1,179,204).

How common is HS6ST2 p.Val8Phe (c.22G>T) in the general population?

HS6ST2 p.Val8Phe (c.22G>T) is no allele count reported in gnomAD v4.1 (AN 1,179,204) (gnomAD).

What do computational predictors say about HS6ST2 p.Val8Phe (c.22G>T)?

AlphaMissense predicts likely benign (score 0.0868) — an in-silico prediction, not a clinical call.

HS6ST2 p.Val8Phe

c.22G>T · VCV3526687

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0868 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,179,204)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0868	likely benign
REVEL	0.103	moderately benign-leaning
SaProt	LLR -7.38	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.9	GERP 1.5, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 330 kb · p 0.16 · regional, not allelic
Overall
CADD	23.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,179,204). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: HS6ST2
Protein: p.Val8Phe
Coding: c.22G>T
MANE Select: NM_001394073
Type: single nucleotide variant
Location: chrX:132958581 (GRCh38)
Structure: AlphaFold pLDDT 74.28
Residue 8: the 'disordered' region

Full HS6ST2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HS6ST2 p.Val8fs Benign same residue
HS6ST2 p.Arg9Trp Uncertain significance ★★ ⚠ same type
HS6ST2 p.Gly306Ala Uncertain significance ★★ ⚠ same type
HS6ST2 p.Lys218Gln Uncertain significance ★★ ⚠ same type
HS6ST2 p.Pro581Leu Uncertain significance ★★ ⚠ same type
HS6ST2 p.Ala325= Benign/Likely benign ★★ same type
HS6ST2 p.Arg51Leu Benign ★★ same type
HS6ST2 p.Leu107= Benign ★★ 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/hs6st2-p-val8phe (accessed [today's date]).

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