Is PSPH p.Thr152Ile (c.455C>T) pathogenic?

PSPH p.Thr152Ile (c.455C>T) is classified Conflicting classifications of pathogenicity in PSPH (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-16). AlphaMissense: likely pathogenic (0.8878); Ultra-rare (popmax 0.0892%, nfe); Associated with PSPH deficiency.

What condition is associated with PSPH p.Thr152Ile (c.455C>T)?

PSPH p.Thr152Ile (c.455C>T) is associated with PSPH deficiency (ClinVar).

How common is PSPH p.Thr152Ile (c.455C>T) in the general population?

PSPH p.Thr152Ile (c.455C>T) is ultra-rare (popmax 0.0892%, nfe) (gnomAD).

What do computational predictors say about PSPH p.Thr152Ile (c.455C>T)?

AlphaMissense predicts likely pathogenic (score 0.8878) — an in-silico prediction, not a clinical call.

PSPH p.Thr152Ile

c.455C>T · rs147304638 · VCV360505

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.8878 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0892%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

PSPH deficiency

Computational evidence

Protein change
AlphaMissense	0.8878	likely pathogenic
REVEL	0.551	indeterminate
SaProt	LLR -12.94	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 4.2, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 9,447 bp · p 0.0022 · regional, not allelic
Overall
CADD	26.5	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 0.0892% European (non-Finnish) · 1,053/1,179,986 alleles

Filtering AF 0.0847% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0829%

Overall 0.0897% 1,447/1,613,986 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.709%	141
Remaining individualsnot grpmax-eligible	0.126%	791
Finnishnot grpmax-eligible	0.123%	810
European (non-Finnish)grpmax	0.0892%	1,121
Admixed American	0.0167%	5,998
Middle Eastern	0.0165%	6,062
South Asian	0.00988%	10,118
African / African-American	0.008%	12,501

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: PSPH
Protein: p.Thr152Ile
Coding: c.455C>T
MANE Select: NM_004577
dbSNP: rs147304638
Type: single nucleotide variant
Location: chr7:56015138 (GRCh38)
Gene constraint: LOEUF 1.063 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 92.88 · 6 PDB
Residue 152: an α-helix

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

Disease context

PSPH deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PSPH p.Arg101Ter Likely pathogenic ★★ same condition
PSPH c.422-3A>C Uncertain significance ★★ same condition
PSPH c.570+3A>G Uncertain significance ★★ same condition
PSPH c.570+5G>C Uncertain significance ★★ same condition
PSPH c.*341G>A Uncertain significance ★★ same condition
PSPH p.Asn124Ser Uncertain significance ★★ ⚠ same condition
PSPH p.Asp32Asn Uncertain significance ★★ ⚠ same condition
PSPH p.Gln204His 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/psph-p-thr152ile (accessed [today's date]).

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