Is HSPH1 p.Pro320Ser (c.958C>T) pathogenic?

HSPH1 p.Pro320Ser (c.958C>T) is classified Uncertain significance in HSPH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-10). AlphaMissense: likely benign (0.3153); Very rare (popmax 0.00134%, afr).

How common is HSPH1 p.Pro320Ser (c.958C>T) in the general population?

HSPH1 p.Pro320Ser (c.958C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about HSPH1 p.Pro320Ser (c.958C>T)?

AlphaMissense predicts likely benign (score 0.3153) — an in-silico prediction, not a clinical call.

HSPH1 p.Pro320Ser

c.958C>T · VCV3527049

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3153 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.3153	likely benign
REVEL	0.393	indeterminate
SaProt	LLR -12.13	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.9	GERP 1.3, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 24 kb · p 1.3e-05 · regional, not allelic
Overall
CADD	26.2	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 0.00134% African / African-American · 1/74,830 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,611,034 alleles · very rare exomes 1/1,458,892 · genomes 2/152,142 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,830
European (non-Finnish)	0.00017%	588,932

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: HSPH1
Protein: p.Pro320Ser
Coding: c.958C>T
MANE Select: NM_006644
Type: single nucleotide variant
Location: chr13:31150133 (GRCh38)
Gene constraint: LOEUF 0.435 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.31 · 1 PDB
Residue 320: an α-helix

Full HSPH1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HSPH1 p.Ala344Ser Uncertain significance ★★ ⚠ same type
HSPH1 p.Arg781His Benign/Likely benign ★★ same type
HSPH1 p.Asp32= Likely benign ★★ same type
HSPH1 p.Glu575= Benign ★★ same type
HSPH1 p.Leu435Val Benign ★★ same type
HSPH1 p.Ala18Gly Uncertain significance ★ ⚠ same type
HSPH1 p.Ala18Ser Uncertain significance ★ ⚠ same type
HSPH1 p.Ala18Val 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/hsph1-p-pro320ser (accessed [today's date]).

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