Is EEFSEC p.Met1Val (c.1A>G) pathogenic?

EEFSEC p.Met1Val (c.1A>G) is classified Pathogenic in EEFSEC (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-02-25). Very rare (popmax 0.00147%, afr); Associated with neurodevelopmental disorder with progressive spasticity and brain abnormalities.

How common is EEFSEC p.Met1Val (c.1A>G) in the general population?

EEFSEC p.Met1Val (c.1A>G) is very rare (popmax 0.00147%, afr) (gnomAD).

EEFSEC p.Met1Val

Q: What condition is associated with EEFSEC p.Met1Val (c.1A>G)?

EEFSEC p.Met1Val (c.1A>G) is associated with neurodevelopmental disorder with progressive spasticity and brain abnormalities (ClinVar).

c.1A>G · VCV3764735

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00147%, afr)

Conditions

neurodevelopmental disorder with progressive spasticity and brain abnormalities

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function
REVEL	0.246	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 2, phastCons 1
Overall
CADD	20.4	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00147% African / African-American · 1/68,238 alleles

Overall 6.68e-05% 1/1,497,132 alleles · very rare exomes 1/1,345,654 · genomes 0/151,478 · 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: EEFSEC
Protein: p.Met1Val
Coding: c.1A>G
MANE Select: NM_021937
Type: single nucleotide variant
Location: chr3:128153508 (GRCh38)
Gene constraint: LOEUF 1.345 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.98 · 4 PDB

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

Disease context

neurodevelopmental disorder with progressive spasticity and brain abnormalities — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EEFSEC p.Arg285Gln Uncertain significance ★★ ⚠ same condition
EEFSEC p.Glu514Ter Likely pathogenic ★ same condition
EEFSEC p.Leu246Pro Uncertain significance ★ ⚠ same condition
EEFSEC p.Pro194Thr Conflicting classifications of pathogenicity ★ ⚠ same condition
EEFSEC p.Cys426Ter Pathogenic same condition
EEFSEC p.Val585fs Likely pathogenic ★ same condition
EEFSEC p.Arg424Gln Uncertain significance ★★ ⚠ same type
EEFSEC p.Phe463Leu Uncertain significance ★★ ⚠ same type

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/eefsec-p-met1val (accessed [today's date]).

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