Is ERF p.Met76Val (c.226A>G) pathogenic?

ERF p.Met76Val (c.226A>G) is classified Uncertain significance in ERF (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-29). AlphaMissense: likely pathogenic (0.9974); Absent from gnomAD v4.1; Associated with Lambdoidal craniosynostosis.

What condition is associated with ERF p.Met76Val (c.226A>G)?

ERF p.Met76Val (c.226A>G) is associated with Lambdoidal craniosynostosis (ClinVar).

How common is ERF p.Met76Val (c.226A>G) in the general population?

ERF p.Met76Val (c.226A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ERF p.Met76Val (c.226A>G)?

AlphaMissense predicts likely pathogenic (score 0.9974) — an in-silico prediction, not a clinical call.

ERF p.Met76Val

c.226A>G · rs2513525499 · VCV1707521

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9974 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Lambdoidal craniosynostosis

Computational evidence

Protein change
AlphaMissense	0.9974	likely pathogenic · top 8% in ERF
REVEL	0.765	pathogenic-leaning
SaProt	LLR -14.57	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.95	donor gain · deltas
Pangolin	Δ0.76	gain · loss 0.50 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 6.2	GERP 1.8, phastCons 1
Regional constraint	o/e 0.22	constrained · MANE · 558 bp · p 2.8e-12 · regional, not allelic
Overall
CADD	36.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ERF
Protein: p.Met76Val
Coding: c.226A>G
MANE Select: NM_006494
dbSNP: rs2513525499
Type: single nucleotide variant
Location: chr19:42250362 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 55.46 · 2 PDB
Residue 76: a DNA-binding region

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

Disease context

Lambdoidal craniosynostosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ERF p.Met76Lys Uncertain significance ★ ⚠ same residue
ERF p.Met76Thr Uncertain significance ★★ ⚠ same residue
ERF p.Met76Ile Uncertain significance ★ ⚠ same residue
ERF p.Ser24Ter Pathogenic/Likely pathogenic ★★ same condition
ERF p.Trp14Ter Likely pathogenic ★★ same condition
ERF p.Arg180Cys Uncertain significance ★★ ⚠ same condition
ERF p.Gln49Ter Likely pathogenic ★ same condition
ERF p.Gly53Ala 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/erf-p-met76val (accessed [today's date]).

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