Is PSPH p.Phe216Cys (c.647T>G) pathogenic?

PSPH p.Phe216Cys (c.647T>G) is classified Uncertain significance in PSPH (ClinVar, Single submitter, 1 submitter; last evaluated 2021-05-21). AlphaMissense: likely pathogenic (0.905); Very rare (popmax 0.00133%, afr); Associated with PSPH deficiency.

What condition is associated with PSPH p.Phe216Cys (c.647T>G)?

PSPH p.Phe216Cys (c.647T>G) is associated with PSPH deficiency (ClinVar).

How common is PSPH p.Phe216Cys (c.647T>G) in the general population?

PSPH p.Phe216Cys (c.647T>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about PSPH p.Phe216Cys (c.647T>G)?

AlphaMissense predicts likely pathogenic (score 0.905) — an in-silico prediction, not a clinical call.

PSPH p.Phe216Cys

c.647T>G · rs935820820 · VCV1379226

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.905 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PSPH deficiency

Computational evidence

Protein change
AlphaMissense	0.905	likely pathogenic
REVEL	0.926	moderately pathogenic-leaning
SaProt	LLR -13.39	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 11	GERP 4.3, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 9,447 bp · p 0.0022 · regional, not allelic
Overall
CADD	25.5	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 0.00133% African / African-American · 1/74,912 alleles

Overall 6.2e-05% 1/1,613,356 alleles · very rare exomes 0/1,461,160 · genomes 1/152,196 · joint denominator

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.Phe216Cys
Coding: c.647T>G
MANE Select: NM_004577
dbSNP: rs935820820
Type: single nucleotide variant
Location: chr7:56011793 (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 216: 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-phe216cys (accessed [today's date]).

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