Is ECHDC2 p.Arg240Trp (c.718C>T) pathogenic?

ECHDC2 p.Arg240Trp (c.718C>T) is classified Uncertain significance in ECHDC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-26). AlphaMissense: likely benign (0.2328); Very rare (popmax 0.00538%, afr).

How common is ECHDC2 p.Arg240Trp (c.718C>T) in the general population?

ECHDC2 p.Arg240Trp (c.718C>T) is very rare (popmax 0.00538%, afr) (gnomAD).

What do computational predictors say about ECHDC2 p.Arg240Trp (c.718C>T)?

AlphaMissense predicts likely benign (score 0.2328) — an in-silico prediction, not a clinical call.

ECHDC2 p.Arg240Trp

c.718C>T · VCV4246361

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2328 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00538%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2328	likely benign
REVEL	0.733	pathogenic-leaning
SaProt	LLR -10.65	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.26 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.2	GERP -2.2, phastCons 0.94
Regional constraint	o/e 0.98	unconstrained · MANE · 25 kb · p 0.66 · regional, not allelic
Overall
CADD	27.9	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 0.00538% African / African-American · 4/74,392 alleles

Filtering AF 0.00176% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00105%

Overall 0.000434% 7/1,613,424 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00538%	18,598
East Asian	0.00223%	44,826
South Asian	0.0011%	91,070
European (non-Finnish)	8.47e-05%	1,180,034

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: ECHDC2
Protein: p.Arg240Trp
Coding: c.718C>T
MANE Select: NM_001198961
Type: single nucleotide variant
Location: chr1:52899209 (GRCh38)
Gene constraint: LOEUF 1.033 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.28

Full ECHDC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ECHDC2 p.Ala105Val Uncertain significance ★ ⚠ same type
ECHDC2 p.Ala131Val Uncertain significance ★ ⚠ same type
ECHDC2 p.Ala152Thr Uncertain significance ★ ⚠ same type
ECHDC2 p.Ala201Gly Uncertain significance ★ ⚠ same type
ECHDC2 p.Ala20Pro Uncertain significance ★ ⚠ same type
ECHDC2 p.Ala20Thr Uncertain significance ★ ⚠ same type
ECHDC2 p.Ala210Thr Uncertain significance ★ ⚠ same type
ECHDC2 p.Ala219Thr 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/echdc2-p-arg240trp (accessed [today's date]).

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