Is EEFSEC p.Leu246Pro (c.737T>C) pathogenic?

EEFSEC p.Leu246Pro (c.737T>C) is classified Uncertain significance in EEFSEC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-22). AlphaMissense: likely pathogenic (0.9889); Absent from gnomAD v4.1; Associated with neurodevelopmental disorder with progressive spasticity and brain abnormalities.

How common is EEFSEC p.Leu246Pro (c.737T>C) in the general population?

EEFSEC p.Leu246Pro (c.737T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EEFSEC p.Leu246Pro (c.737T>C)?

AlphaMissense predicts likely pathogenic (score 0.9889) — an in-silico prediction, not a clinical call.

EEFSEC p.Leu246Pro

Q: What condition is associated with EEFSEC p.Leu246Pro (c.737T>C)?

EEFSEC p.Leu246Pro (c.737T>C) is associated with neurodevelopmental disorder with progressive spasticity and brain abnormalities (ClinVar).

c.737T>C · VCV4855262

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9889 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neurodevelopmental disorder with progressive spasticity and brain abnormalities

Computational evidence

Protein change
AlphaMissense	0.9889	likely pathogenic · top 8% in EEFSEC
REVEL	0.793	moderately pathogenic-leaning
SaProt	LLR -12.08	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.3, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 255 kb · p 0.039 · regional, not allelic
Overall
CADD	31.0	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: EEFSEC
Protein: p.Leu246Pro
Coding: c.737T>C
MANE Select: NM_021937
Type: single nucleotide variant
Location: chr3:128264732 (GRCh38)
Gene constraint: LOEUF 1.345 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.98 · 4 PDB
Residue 246: a β-strand

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.Pro194Thr Conflicting classifications of pathogenicity ★ ⚠ same condition
EEFSEC p.Cys426Ter Pathogenic same condition
EEFSEC p.Met1Val 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-leu246pro (accessed [today's date]).

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