Is ECT2L p.Ser248Leu (c.743C>T) pathogenic?

ECT2L p.Ser248Leu (c.743C>T) is classified Uncertain significance in ECT2L (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-22). AlphaMissense: likely benign (0.152); Ultra-rare (popmax 0.0164%, mid).

How common is ECT2L p.Ser248Leu (c.743C>T) in the general population?

ECT2L p.Ser248Leu (c.743C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about ECT2L p.Ser248Leu (c.743C>T)?

AlphaMissense predicts likely benign (score 0.152) — an in-silico prediction, not a clinical call.

ECT2L p.Ser248Leu

c.743C>T · rs766879877 · VCV2343768

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.152 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.152	likely benign
REVEL	0.315	indeterminate
SaProt	LLR -7.92	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.28	donor loss · deltas
Constraint at this position
Conservation	phyloP 4.8	GERP 2.2, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 89 kb · p 0.11 · regional, not allelic
Overall
CADD	25.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00217%

Overall 0.00291% 47/1,613,938 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Admixed American	0.005%	19,999
European (non-Finnish)	0.00331%	30,256
South Asian	0.0022%	45,533
Remaining individualsnot grpmax-eligible	0.0016%	62,486
Finnishnot grpmax-eligible	0.00156%	64,026

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: ECT2L
Protein: p.Ser248Leu
Coding: c.743C>T
MANE Select: NM_001077706
dbSNP: rs766879877
Type: single nucleotide variant
Location: chr6:138844559 (GRCh38)
Gene constraint: LOEUF 1.127 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.75 · 1 PDB

Full ECT2L gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ECT2L p.Ala147Thr Uncertain significance ★ ⚠ same type
ECT2L p.Ala161Thr Uncertain significance ★ ⚠ same type
ECT2L p.Ala299Val Uncertain significance ★ ⚠ same type
ECT2L p.Ala401Ser Uncertain significance ★ ⚠ same type
ECT2L p.Ala443Ser Uncertain significance ★ ⚠ same type
ECT2L p.Ala515Gly Uncertain significance ★ ⚠ same type
ECT2L p.Ala599Thr Uncertain significance ★ ⚠ same type
ECT2L p.Ala605Gly 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/ect2l-p-ser248leu (accessed [today's date]).

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