Is PSPH p.Leu68= (c.204C>A) pathogenic?

PSPH p.Leu68= (c.204C>A) is classified Benign in PSPH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-03-31). Common (popmax 43.4%, afr) — too common for a highly-penetrant pathogenic allele; Associated with PSPH deficiency.

What condition is associated with PSPH p.Leu68= (c.204C>A)?

PSPH p.Leu68= (c.204C>A) is associated with PSPH deficiency (ClinVar).

PSPH p.Leu68=

Q: How common is PSPH p.Leu68= (c.204C>A) in the general population?

PSPH p.Leu68= (c.204C>A) is common (popmax 43.4%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.204C>A · rs201644817 · VCV910295

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

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

Conditions

PSPH deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.84	GERP 0.68, phastCons 1
Overall
CADD	6.672	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 43.4% African / African-American · 24,339/56,062 alleles

Filtering AF 43% ClinGen BA1/BS1 input FAF95, joint · FAF99 42.8%

Overall 6.55% 81,953/1,250,274 alleles · common exomes 45,864/1,111,096 · genomes 36,089/139,178 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	43.4%	2
East Asian	35.3%	3
Admixed American	14.7%	7
South Asian	14.5%	7
Finnishnot grpmax-eligible	11.7%	9
Middle Eastern	10%	10
Amishnot grpmax-eligible	6.98%	14
Remaining individualsnot grpmax-eligible	6.23%	16
Ashkenazi Jewishnot grpmax-eligible	4.11%	24
European (non-Finnish)	2.62%	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.Leu68=
Coding: c.204C>A
MANE Select: NM_004577
dbSNP: rs201644817
Type: single nucleotide variant
Location: chr7:56019671 (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.Leu68Pro 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-leu68 (accessed [today's date]).

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