Is PSPH p.Val217Ala (c.650T>C) pathogenic?

PSPH p.Val217Ala (c.650T>C) is classified Conflicting classifications of pathogenicity in PSPH (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0627); Low-frequency (popmax 2.39%, afr); Associated with PSPH deficiency.

What condition is associated with PSPH p.Val217Ala (c.650T>C)?

PSPH p.Val217Ala (c.650T>C) is associated with PSPH deficiency (ClinVar).

How common is PSPH p.Val217Ala (c.650T>C) in the general population?

PSPH p.Val217Ala (c.650T>C) is low-frequency (popmax 2.39%, afr) (gnomAD).

What do computational predictors say about PSPH p.Val217Ala (c.650T>C)?

AlphaMissense predicts likely benign (score 0.0627) — an in-silico prediction, not a clinical call.

PSPH p.Val217Ala

c.650T>C · rs73343752 · VCV391900

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0627 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.39%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PSPH deficiency

Computational evidence

Protein change
AlphaMissense	0.0627	likely benign
REVEL	0.121	moderately benign-leaning
SaProt	LLR -4.24	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 3.2, phastCons 0.99
Regional constraint	o/e 0.81	unconstrained · MANE · 9,447 bp · p 0.0022 · regional, not allelic
Overall
CADD	8.659	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 2.39% African / African-American · 1,794/75,010 alleles

Filtering AF 2.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.26%

Overall 0.132% 2,122/1,613,360 alleles · low-frequency exomes 1,024/1,461,044 · genomes 1,098/152,316 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.39%	42
Admixed American	0.212%	472
Remaining individualsnot grpmax-eligible	0.192%	521
Middle Eastern	0.0661%	1,513
South Asian	0.0121%	8,279
European (non-Finnish)	0.00551%	18,144
East Asian	0.00223%	44,862

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.Val217Ala
Coding: c.650T>C
MANE Select: NM_004577
dbSNP: rs73343752
Type: single nucleotide variant
Location: chr7:56011790 (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 217: 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.Val217= 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-val217ala (accessed [today's date]).

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