Is PRDM5 p.Met4Arg (c.11T>G) pathogenic?

PRDM5 p.Met4Arg (c.11T>G) is classified Uncertain significance in PRDM5 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-04-29). AlphaMissense: likely pathogenic (0.688); Very rare (popmax 8.49e-05%, nfe); Associated with brittle cornea syndrome 2.

What condition is associated with PRDM5 p.Met4Arg (c.11T>G)?

PRDM5 p.Met4Arg (c.11T>G) is associated with brittle cornea syndrome 2 (ClinVar).

How common is PRDM5 p.Met4Arg (c.11T>G) in the general population?

PRDM5 p.Met4Arg (c.11T>G) is very rare (popmax 8.49e-05%, nfe) (gnomAD).

How is Brittle cornea syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PRDM5 p.Met4Arg (c.11T>G)?

AlphaMissense predicts likely pathogenic (score 0.688) — an in-silico prediction, not a clinical call.

PRDM5 p.Met4Arg

c.11T>G · rs1002440008 · VCV2132841

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.688 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

brittle cornea syndrome 2

Computational evidence

Protein change
AlphaMissense	0.688	likely pathogenic
REVEL	0.624	indeterminate
SaProt	LLR -5.13	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	Δ0.81	donor gain · deltas
Pangolin	Δ0.32	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 10	GERP 1.3, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 145 kb · p 0.23 · regional, not allelic
Overall
CADD	33.0	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 8.49e-05% European (non-Finnish) · 1/1,177,576 alleles

Overall 6.22e-05% 1/1,607,036 alleles · very rare exomes 1/1,455,046 · genomes 0/151,990 · 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: PRDM5
Protein: p.Met4Arg
Coding: c.11T>G
MANE Select: NM_018699
dbSNP: rs1002440008
Type: single nucleotide variant
Location: chr4:120922598 (GRCh38)
Gene constraint: LOEUF 0.899 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.53 · 1 PDB
Residue 4: a β-strand

Full PRDM5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

brittle cornea syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Brittle cornea syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

PRDM5 p.Met4Ile Uncertain significance ★★ ⚠ same residue
PRDM5 c.1623+1G>A Likely pathogenic ★★ same condition
PRDM5 c.865+1G>A Likely pathogenic ★★ same condition
PRDM5 p.Arg232Ter Pathogenic/Likely pathogenic ★★ same condition
PRDM5 p.Arg346Ter Pathogenic ★★ same condition
PRDM5 p.Gln420Ter Pathogenic/Likely pathogenic ★★ same condition
PRDM5 p.Glu103Ter Pathogenic/Likely pathogenic ★★ same condition
PRDM5 p.Glu344Ter Pathogenic/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/prdm5-p-met4arg (accessed [today's date]).

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