Is PSPH p.Leu68Pro (c.203T>C) pathogenic?

PSPH p.Leu68Pro (c.203T>C) is classified Benign in PSPH (ClinVar, Multiple submitters, 4 submitters; last evaluated 2021-03-31). AlphaMissense: likely pathogenic (0.9648); Common (popmax 43.4%, afr) — too common for a highly-penetrant pathogenic allele; Associated with PSPH deficiency.

What condition is associated with PSPH p.Leu68Pro (c.203T>C)?

PSPH p.Leu68Pro (c.203T>C) is associated with PSPH deficiency (ClinVar).

What do computational predictors say about PSPH p.Leu68Pro (c.203T>C)?

AlphaMissense predicts likely pathogenic (score 0.9648) — an in-silico prediction, not a clinical call.

PSPH p.Leu68Pro

Q: How common is PSPH p.Leu68Pro (c.203T>C) in the general population?

PSPH p.Leu68Pro (c.203T>C) is common (popmax 43.4%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.203T>C · rs78067484 · VCV911506

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9648 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 43.4%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PSPH deficiency

Computational evidence

Protein change
AlphaMissense	0.9648	likely pathogenic
REVEL	0.748	pathogenic-leaning
SaProt	LLR -15.85	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.2	GERP 3.7, 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 43.4% African / African-American · 24,289/55,976 alleles

Filtering AF 42.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 42.7%

Overall 6.55% 82,058/1,252,112 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	43.4%	2
East Asian	35.4%	3
Admixed American	14.8%	7
South Asian	14.7%	7
Finnishnot grpmax-eligible	11.7%	9
Middle Eastern	9.87%	10
Amishnot grpmax-eligible	7.08%	14
Remaining individualsnot grpmax-eligible	6.24%	16
Ashkenazi Jewishnot grpmax-eligible	4.11%	24
European (non-Finnish)	2.6%	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.Leu68Pro
Coding: c.203T>C
MANE Select: NM_004577
dbSNP: rs78067484
Type: single nucleotide variant
Location: chr7:56019672 (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 68: 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.Leu68= Benign ★★ same residue
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

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-leu68pro (accessed [today's date]).

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