Is PSPH p.Arg65His (c.194G>A) pathogenic?

PSPH p.Arg65His (c.194G>A) is classified Benign/Likely benign in PSPH (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-02-16). AlphaMissense: likely pathogenic (0.9682); Common (popmax 42.9%, afr) — too common for a highly-penetrant pathogenic allele; Associated with PSPH deficiency.

What condition is associated with PSPH p.Arg65His (c.194G>A)?

PSPH p.Arg65His (c.194G>A) is associated with PSPH deficiency (ClinVar).

What do computational predictors say about PSPH p.Arg65His (c.194G>A)?

AlphaMissense predicts likely pathogenic (score 0.9682) — an in-silico prediction, not a clinical call.

PSPH p.Arg65His

Q: How common is PSPH p.Arg65His (c.194G>A) in the general population?

PSPH p.Arg65His (c.194G>A) is common (popmax 42.9%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.194G>A · rs200442078 · VCV911507

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9682 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 42.9%, 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	0.9682	likely pathogenic
REVEL	0.818	moderately pathogenic-leaning
SaProt	LLR -15.46	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 7.6	GERP 3.7, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 9,447 bp · p 0.0022 · regional, not allelic
Overall
CADD	28.3	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 42.9% African / African-American · 23,485/54,762 alleles

Filtering AF 42.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 42.2%

Overall 6.16% 77,334/1,256,320 alleles · common exomes 40,829/1,116,430 · genomes 36,505/139,890 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	42.9%	2
East Asian	35.1%	3
Admixed American	14.4%	7
South Asian	13.5%	7
Finnishnot grpmax-eligible	11.7%	9
Middle Eastern	10.1%	10
Amishnot grpmax-eligible	7.51%	13
Remaining individualsnot grpmax-eligible	5.75%	17
Ashkenazi Jewishnot grpmax-eligible	3.98%	25
European (non-Finnish)	2.31%	43

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.Arg65His
Coding: c.194G>A
MANE Select: NM_004577
dbSNP: rs200442078
Type: single nucleotide variant
Location: chr7:56019681 (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 65: 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-arg65his (accessed [today's date]).

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