Is PSPH p.Val161Met (c.481G>A) pathogenic?

PSPH p.Val161Met (c.481G>A) is classified Uncertain significance in PSPH (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). AlphaMissense: likely pathogenic (0.7742); Very rare (popmax 0.00446%, eas); Associated with PSPH deficiency.

What condition is associated with PSPH p.Val161Met (c.481G>A)?

PSPH p.Val161Met (c.481G>A) is associated with PSPH deficiency (ClinVar).

How common is PSPH p.Val161Met (c.481G>A) in the general population?

PSPH p.Val161Met (c.481G>A) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about PSPH p.Val161Met (c.481G>A)?

AlphaMissense predicts likely pathogenic (score 0.7742) — an in-silico prediction, not a clinical call.

PSPH p.Val161Met

c.481G>A · rs765086289 · VCV910293

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7742 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

PSPH deficiency

Computational evidence

Protein change
AlphaMissense	0.7742	likely pathogenic
REVEL	0.418	indeterminate
SaProt	LLR -11.29	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 3.3, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 9,447 bp · p 0.0022 · regional, not allelic
Overall
CADD	26.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,876 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.00031% 5/1,614,056 alleles · very rare exomes 5/1,461,778 · genomes 0/152,278 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,438
Remaining individualsnot grpmax-eligible	0.0032%	31,252
South Asian	0.0011%	91,064

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.Val161Met
Coding: c.481G>A
MANE Select: NM_004577
dbSNP: rs765086289
Type: single nucleotide variant
Location: chr7:56015112 (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 161: 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-val161met (accessed [today's date]).

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