Is PRR12 p.Ser592Leu (c.1775C>T) pathogenic?

PRR12 p.Ser592Leu (c.1775C>T) is classified Likely pathogenic in PRR12 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-13). AlphaMissense: likely pathogenic (0.6889); Very rare (popmax 8.48e-05%, nfe); Associated with neuroocular syndrome 1.

What condition is associated with PRR12 p.Ser592Leu (c.1775C>T)?

PRR12 p.Ser592Leu (c.1775C>T) is associated with neuroocular syndrome 1 (ClinVar).

How common is PRR12 p.Ser592Leu (c.1775C>T) in the general population?

PRR12 p.Ser592Leu (c.1775C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about PRR12 p.Ser592Leu (c.1775C>T)?

AlphaMissense predicts likely pathogenic (score 0.6889) — an in-silico prediction, not a clinical call.

PRR12 p.Ser592Leu

c.1775C>T · VCV4850098

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6889 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuroocular syndrome 1

Computational evidence

Protein change
AlphaMissense	0.6889	likely pathogenic ✓ concordant with ClinVar
REVEL	0.085	moderately benign-leaning
SaProt	LLR -8.83	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 7.5	GERP 1.5, phastCons 1
Regional constraint	o/e 0.64	unconstrained · MANE · 222 bp · p 0.00032 · regional, not allelic
Overall
CADD	23.3	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 8.48e-05% European (non-Finnish) · 1/1,179,768 alleles

Overall 6.24e-05% 1/1,603,372 alleles · very rare exomes 1/1,451,008 · genomes 0/152,364 · 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: PRR12
Protein: p.Ser592Leu
Coding: c.1775C>T
MANE Select: NM_020719
Type: single nucleotide variant
Location: chr19:49596110 (GRCh38)
Gene constraint: LOEUF 0.18 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.84
Residue 592: a UniProt-annotated variant site (in noc1)

Full PRR12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Similar variants

PRR12 p.Arg1169Trp Likely pathogenic ★★ ⚠ same condition
PRR12 p.Glu640Ter Pathogenic ★★ same condition
PRR12 p.Thr686Ile Uncertain significance ★★ ⚠ same condition
PRR12 p.Arg1605Ter Likely pathogenic ★ same condition
PRR12 p.Ser1135Ter Likely pathogenic ★ same condition
PRR12 p.Tyr389Ter Pathogenic ★ same condition
PRR12 p.Ala708Val Conflicting classifications of pathogenicity ★ ⚠ same condition
PRR12 p.Asp500Glu 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/prr12-p-ser592leu (accessed [today's date]).

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