Is PSPH p.Ala181Val (c.542C>T) pathogenic?

PSPH p.Ala181Val (c.542C>T) is classified Likely benign in PSPH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-23). AlphaMissense: likely benign (0.2381); Rare (popmax 0.221%, sas); Associated with PSPH deficiency.

What condition is associated with PSPH p.Ala181Val (c.542C>T)?

PSPH p.Ala181Val (c.542C>T) is associated with PSPH deficiency (ClinVar).

How common is PSPH p.Ala181Val (c.542C>T) in the general population?

PSPH p.Ala181Val (c.542C>T) is rare (popmax 0.221%, sas) (gnomAD).

What do computational predictors say about PSPH p.Ala181Val (c.542C>T)?

AlphaMissense predicts likely benign (score 0.2381) — an in-silico prediction, not a clinical call.

PSPH p.Ala181Val

c.542C>T · rs527489732 · VCV1534510

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2381 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.221%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

PSPH deficiency

Computational evidence

Protein change
AlphaMissense	0.2381	likely benign
REVEL	0.306	indeterminate
SaProt	LLR -7.19	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.4	GERP 4.3, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 9,447 bp · p 0.0022 · regional, not allelic
Overall
CADD	21.8	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 0.221% South Asian · 201/91,064 alleles

Filtering AF 0.196% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.186%

Overall 0.0131% 212/1,613,988 alleles · rare exomes 204/1,461,806 · genomes 8/152,182 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.221%	453
Middle Eastern	0.033%	3,030
Remaining individualsnot grpmax-eligible	0.0128%	7,813
African / African-American	0.00133%	74,990

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.Ala181Val
Coding: c.542C>T
MANE Select: NM_004577
dbSNP: rs527489732
Type: single nucleotide variant
Location: chr7:56015051 (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 181: 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-ala181val (accessed [today's date]).

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