Is HS6ST2 p.Ser151Pro (c.451T>C) pathogenic?

HS6ST2 p.Ser151Pro (c.451T>C) is classified Uncertain significance in HS6ST2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-28). AlphaMissense: likely benign (0.2359); Ultra-rare (popmax 0.0144%, afr).

How common is HS6ST2 p.Ser151Pro (c.451T>C) in the general population?

HS6ST2 p.Ser151Pro (c.451T>C) is ultra-rare (popmax 0.0144%, afr) (gnomAD).

What do computational predictors say about HS6ST2 p.Ser151Pro (c.451T>C)?

AlphaMissense predicts likely benign (score 0.2359) — an in-silico prediction, not a clinical call.

HS6ST2 p.Ser151Pro

c.451T>C · VCV4036346

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2359 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0144%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2359	likely benign
REVEL	0.387	indeterminate
SaProt	LLR -8.14	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.8	GERP 0.41, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 330 kb · p 0.16 · regional, not allelic
Overall
CADD	26.3	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

Grpmax group 0.0144% African / African-American · 8/55,604 alleles

Filtering AF 0.00707% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00515%

Overall 0.00129% 15/1,160,856 alleles · ultra-rare exomes 7/1,049,597 · genomes 8/111,259 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0144%	6,950
Remaining individualsnot grpmax-eligible	0.00881%	11,348
Admixed American	0.00743%	13,453

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: HS6ST2
Protein: p.Ser151Pro
Coding: c.451T>C
MANE Select: NM_001394073
Type: single nucleotide variant
Location: chrX:132957304 (GRCh38)
Structure: AlphaFold pLDDT 74.28

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

Similar variants

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
HS6ST2 p.Ala202Ser 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/hs6st2-p-ser151pro (accessed [today's date]).

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