Is OPHN1 p.Phe782Cys (c.2345T>G) pathogenic?

OPHN1 p.Phe782Cys (c.2345T>G) is classified Uncertain significance in OPHN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-14). AlphaMissense: likely pathogenic (0.9168); Very rare (popmax 0.000336%, nfe); Associated with X-linked intellectual disability-cerebellar hypoplasia syndrome.

What condition is associated with OPHN1 p.Phe782Cys (c.2345T>G)?

OPHN1 p.Phe782Cys (c.2345T>G) is associated with X-linked intellectual disability-cerebellar hypoplasia syndrome (ClinVar).

How common is OPHN1 p.Phe782Cys (c.2345T>G) in the general population?

OPHN1 p.Phe782Cys (c.2345T>G) is very rare (popmax 0.000336%, nfe) (gnomAD).

What do computational predictors say about OPHN1 p.Phe782Cys (c.2345T>G)?

AlphaMissense predicts likely pathogenic (score 0.9168) — an in-silico prediction, not a clinical call.

OPHN1 p.Phe782Cys

Q: How is X-linked intellectual disability-cerebellar hypoplasia syndrome inherited?

Typically X-linked dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.2345T>G · VCV4079474

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9168 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000336%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

X-linked intellectual disability-cerebellar hypoplasia syndrome

Computational evidence

Protein change
AlphaMissense	0.9168	likely pathogenic
REVEL	0.217	benign-leaning
SaProt	LLR -8.99	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.3, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 25 kb · p 0.063 · regional, not allelic
Overall
CADD	26.8	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 0.000336% European (non-Finnish) · 3/893,768 alleles

Filtering AF 8.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.5e-05%

Overall 0.000248% 3/1,208,391 alleles · very rare exomes 3/1,094,597 · genomes 0/113,794 · 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: OPHN1
Protein: p.Phe782Cys
Coding: c.2345T>G
MANE Select: NM_002547
Type: single nucleotide variant
Location: chrX:68052570 (GRCh38)
Structure: AlphaFold pLDDT 74.86

Full OPHN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

X-linked intellectual disability-cerebellar hypoplasia syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For X-linked intellectual disability-cerebellar hypoplasia syndrome (Orphanet):

Inheritance: X-linked dominant
Onset: Infancy, Neonatal

Similar variants

OPHN1 c.1138+1G>A Pathogenic ★★ same condition
OPHN1 c.1202-1G>A Likely pathogenic ★★ same condition
OPHN1 c.155-2A>C Likely pathogenic ★★ same condition
OPHN1 p.Arg497Ter Pathogenic ★★ same condition
OPHN1 p.Gln416Ter Pathogenic ★★ same condition
OPHN1 p.Thr326Met Likely pathogenic ★★ ⚠ same condition
OPHN1 p.Arg788Gln Uncertain significance ★★ ⚠ same condition
OPHN1 p.Asp538Gly 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/ophn1-p-phe782cys (accessed [today's date]).

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