Is OCLN p.Phe219Ser (c.656T>C) pathogenic?

OCLN p.Phe219Ser (c.656T>C) is classified Pathogenic in OCLN (ClinVar, No assertion criteria, 1 submitter; last evaluated 2010-09-10). AlphaMissense: likely pathogenic (0.9509); Very rare (popmax 0.000339%, nfe); Associated with pseudo-TORCH syndrome 1.

What condition is associated with OCLN p.Phe219Ser (c.656T>C)?

OCLN p.Phe219Ser (c.656T>C) is associated with pseudo-TORCH syndrome 1 (ClinVar).

How common is OCLN p.Phe219Ser (c.656T>C) in the general population?

OCLN p.Phe219Ser (c.656T>C) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about OCLN p.Phe219Ser (c.656T>C)?

AlphaMissense predicts likely pathogenic (score 0.9509) — an in-silico prediction, not a clinical call.

OCLN p.Phe219Ser

c.656T>C · rs267606926 · VCV6752

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9509 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

pseudo-TORCH syndrome 1

Computational evidence

Protein change
AlphaMissense	0.9509	likely pathogenic ✓ concordant with ClinVar · top 6% in OCLN
REVEL	0.575	indeterminate
SaProt	LLR -7.87	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.6	phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 9,860 bp · p 0.0048 · regional, not allelic
Overall
CADD	23.7	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 0.000339% European (non-Finnish) · 4/1,180,010 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,614,166 alleles · very rare exomes 4/1,461,852 · genomes 0/152,314 · 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: OCLN
Protein: p.Phe219Ser
Coding: c.656T>C
MANE Select: NM_001205254
dbSNP: rs267606926
Type: single nucleotide variant
Location: chr5:69509746 (GRCh38)
Gene constraint: LOEUF 0.728 · pLI 0.02 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 65.82 · 3 PDB
Residue 219: the marvel domain; a UniProt-annotated variant site (in ptorch1)

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

Disease context

pseudo-TORCH syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

OCLN c.1037+1G>A Pathogenic/Likely pathogenic ★★ same condition
OCLN p.Arg36Ter Pathogenic ★★ same condition
OCLN p.Thr158Ala Uncertain significance ★★ ⚠ same condition
OCLN p.Thr59Pro Uncertain significance ★★ ⚠ same condition
OCLN p.Pro24Ala Benign/Likely benign ★★ same condition
OCLN c.1037+5G>A Pathogenic ★ same condition
OCLN c.1254-1G>A Likely pathogenic ★ same condition
OCLN c.50+2T>C Likely pathogenic ★ 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/ocln-p-phe219ser (accessed [today's date]).

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