Is PSPH p.Pro57Ser (c.169C>T) pathogenic?

PSPH p.Pro57Ser (c.169C>T) is classified Benign in PSPH (ClinVar, Multiple submitters, 4 submitters; last evaluated 2021-03-31). AlphaMissense: likely benign (0.1506); Common (popmax 42.8%, afr) — too common for a highly-penetrant pathogenic allele; Associated with PSPH deficiency.

What condition is associated with PSPH p.Pro57Ser (c.169C>T)?

PSPH p.Pro57Ser (c.169C>T) is associated with PSPH deficiency (ClinVar).

What do computational predictors say about PSPH p.Pro57Ser (c.169C>T)?

AlphaMissense predicts likely benign (score 0.1506) — an in-silico prediction, not a clinical call.

PSPH p.Pro57Ser

Q: How common is PSPH p.Pro57Ser (c.169C>T) in the general population?

PSPH p.Pro57Ser (c.169C>T) is common (popmax 42.8%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.169C>T · rs79321413 · VCV911509

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1506 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 42.8%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PSPH deficiency

Computational evidence

Protein change
AlphaMissense	0.1506	likely benign
REVEL	0.216	benign-leaning
SaProt	LLR -10.44	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.5	GERP 3.7, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 9,447 bp · p 0.0022 · regional, not allelic
Overall
CADD	20.4	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 42.8% African / African-American · 24,258/56,734 alleles

Filtering AF 42.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 42.1%

Overall 6.63% 84,850/1,278,842 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	42.8%	2
East Asian	36%	3
Admixed American	16%	6
South Asian	15%	7
Finnishnot grpmax-eligible	12.6%	8
Middle Eastern	10.8%	9
Amishnot grpmax-eligible	8.14%	12
Remaining individualsnot grpmax-eligible	6.23%	16
Ashkenazi Jewishnot grpmax-eligible	4.41%	23
European (non-Finnish)	2.61%	38

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.Pro57Ser
Coding: c.169C>T
MANE Select: NM_004577
dbSNP: rs79321413
Type: single nucleotide variant
Location: chr7:56019706 (GRCh38)
Gene constraint: LOEUF 1.063 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 92.88 · 6 PDB

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-pro57ser (accessed [today's date]).

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