Is PSPH p.Pro84His (c.251C>A) pathogenic?

PSPH p.Pro84His (c.251C>A) is classified Uncertain significance in PSPH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-05). AlphaMissense: ambiguous (0.3773); Ultra-rare (popmax 0.0111%, eas); Associated with Inborn genetic diseases.

What condition is associated with PSPH p.Pro84His (c.251C>A)?

PSPH p.Pro84His (c.251C>A) is associated with Inborn genetic diseases (ClinVar).

How common is PSPH p.Pro84His (c.251C>A) in the general population?

PSPH p.Pro84His (c.251C>A) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

What do computational predictors say about PSPH p.Pro84His (c.251C>A)?

AlphaMissense predicts ambiguous (score 0.3773) — an in-silico prediction, not a clinical call.

PSPH p.Pro84His

c.251C>A · VCV4146719

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3773 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3773	ambiguous
REVEL	0.479	indeterminate
SaProt	LLR -12.45	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 3.7, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 9,447 bp · p 0.0022 · regional, not allelic
Overall
CADD	24.2	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 0.0111% East Asian · 5/44,884 alleles

Filtering AF 0.00434% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.000342% 5/1,461,524 alleles · ultra-rare

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.Pro84His
Coding: c.251C>A
MANE Select: NM_004577
Type: single nucleotide variant
Location: chr7:56019624 (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 84: an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PSPH p.Asn124Ser Uncertain significance ★★ ⚠ same condition
PSPH p.Glu117Asp Uncertain significance ★★ ⚠ same condition
PSPH p.Glu225Lys Uncertain significance ★★ ⚠ same condition
PSPH p.Tyr212Cys Uncertain significance ★★ ⚠ same condition
PSPH p.Ala192Thr Uncertain significance ★ ⚠ same condition
PSPH p.Ala192Val Conflicting classifications of pathogenicity ★ ⚠ same condition
PSPH p.Ala209Thr Uncertain significance ★ ⚠ same condition
PSPH p.Ala43Val 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-pro84his (accessed [today's date]).

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