Is PSPH p.Arg49Trp (c.145C>T) pathogenic?

PSPH p.Arg49Trp (c.145C>T) is classified Benign in PSPH (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). AlphaMissense: ambiguous (0.3969); Common (popmax 42.5%, afr) — too common for a highly-penetrant pathogenic allele; Associated with PSPH deficiency.

What condition is associated with PSPH p.Arg49Trp (c.145C>T)?

PSPH p.Arg49Trp (c.145C>T) is associated with PSPH deficiency (ClinVar).

What do computational predictors say about PSPH p.Arg49Trp (c.145C>T)?

AlphaMissense predicts ambiguous (score 0.3969) — an in-silico prediction, not a clinical call.

PSPH p.Arg49Trp

Q: How common is PSPH p.Arg49Trp (c.145C>T) in the general population?

PSPH p.Arg49Trp (c.145C>T) is common (popmax 42.5%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.145C>T · rs79451216 · VCV360510

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3969 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 42.5%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

PSPH deficiency

Computational evidence

Protein change
AlphaMissense	0.3969	ambiguous
REVEL	0.595	indeterminate
SaProt	LLR -14.20	damaging
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.36 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.6	GERP 2.8, phastCons 0.99
Regional constraint	o/e 0.81	unconstrained · MANE · 9,447 bp · p 0.0022 · regional, not allelic
Overall
CADD	22.1	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 42.5% African / African-American · 25,039/58,912 alleles

Filtering AF 42.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 41.9%

Overall 7.04% 92,513/1,314,256 alleles · common exomes 54,534/1,171,454 · genomes 37,979/142,802 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	42.5%	2
East Asian	36.1%	3
Admixed American	17.5%	6
South Asian	16.1%	6
Finnishnot grpmax-eligible	13.4%	7
Middle Eastern	10.9%	9
Amishnot grpmax-eligible	8.03%	12
Remaining individualsnot grpmax-eligible	6.72%	15
Ashkenazi Jewishnot grpmax-eligible	4.9%	20
European (non-Finnish)	2.9%	35

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.Arg49Trp
Coding: c.145C>T
MANE Select: NM_004577
dbSNP: rs79451216
Type: single nucleotide variant
Location: chr7:56019730 (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.Arg49Gln Likely 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-arg49trp (accessed [today's date]).

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