Is HSPD1 p.Phe128= (c.384C>T) pathogenic?

HSPD1 p.Phe128= (c.384C>T) is classified Benign/Likely benign in HSPD1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-03). Rare (popmax 0.202%, amr); Associated with Spastic paraplegia.

What condition is associated with HSPD1 p.Phe128= (c.384C>T)?

HSPD1 p.Phe128= (c.384C>T) is associated with Spastic paraplegia (ClinVar).

How common is HSPD1 p.Phe128= (c.384C>T) in the general population?

HSPD1 p.Phe128= (c.384C>T) is rare (popmax 0.202%, amr) (gnomAD).

HSPD1 p.Phe128=

c.384C>T · rs762474761 · VCV697485

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.202%, amr)

Conditions

Spastic paraplegia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP -5.1	GERP -3.7
Overall
CADD	4.618	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.202% Admixed American · 121/59,998 alleles

Filtering AF 0.172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.161%

Overall 0.0125% 201/1,613,918 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.202%	496
Remaining individualsnot grpmax-eligible	0.008%	12,496
European (non-Finnish)	0.00602%	16,619
Finnishnot grpmax-eligible	0.00312%	32,008
East Asian	0.00223%	44,902
African / African-American	0.00133%	74,916

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: HSPD1
Protein: p.Phe128=
Coding: c.384C>T
MANE Select: NM_002156
dbSNP: rs762474761
Type: single nucleotide variant
Location: chr2:197497183 (GRCh38)
Gene constraint: LOEUF 0.185 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 88.21 · 31 PDB
Residue 128: an α-helix

Full HSPD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Spastic paraplegia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HSPD1 p.Ala476Ser Uncertain significance ★★ ⚠ same condition
HSPD1 p.Arg221Gln Uncertain significance ★★ ⚠ same condition
HSPD1 p.Arg37Gln Uncertain significance ★★ ⚠ same condition
HSPD1 p.Asn103Ser Uncertain significance ★★ ⚠ same condition
HSPD1 p.Asn208Thr Uncertain significance ★★ ⚠ same condition
HSPD1 p.Cys442Arg Uncertain significance ★★ ⚠ same condition
HSPD1 p.Glu129Lys Uncertain significance ★★ ⚠ same condition
HSPD1 p.Gly407Ser 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/hspd1-p-phe128 (accessed [today's date]).

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