Is ECHDC3 p.Val140Ile (c.418G>A) pathogenic?

ECHDC3 p.Val140Ile (c.418G>A) is classified Uncertain significance in ECHDC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-04). AlphaMissense: likely benign (0.1002); Ultra-rare (popmax 0.0209%, sas).

How common is ECHDC3 p.Val140Ile (c.418G>A) in the general population?

ECHDC3 p.Val140Ile (c.418G>A) is ultra-rare (popmax 0.0209%, sas) (gnomAD).

What do computational predictors say about ECHDC3 p.Val140Ile (c.418G>A)?

AlphaMissense predicts likely benign (score 0.1002) — an in-silico prediction, not a clinical call.

ECHDC3 p.Val140Ile

c.418G>A · rs373480689 · VCV3086946

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1002 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0209%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1002	likely benign
REVEL	0.226	benign-leaning
SaProt	LLR -10.49	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 2.1, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 21 kb · p 0.0091 · regional, not allelic
Overall
CADD	19.12	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 0.0209% South Asian · 19/91,048 alleles

Filtering AF 0.0136% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0114%

Overall 0.00397% 64/1,613,294 alleles · ultra-rare exomes 57/1,461,406 · genomes 7/151,888 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0209%	4,792
Remaining individualsnot grpmax-eligible	0.016%	6,246
East Asian	0.00446%	22,428
European (non-Finnish)	0.00263%	38,052
Admixed American	0.00167%	59,954
African / African-American	0.00134%	74,820

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: ECHDC3
Protein: p.Val140Ile
Coding: c.418G>A
MANE Select: NM_024693
dbSNP: rs373480689
Type: single nucleotide variant
Location: chr10:11755435 (GRCh38)
Gene constraint: LOEUF 1.614 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.44 · 1 PDB

Full ECHDC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ECHDC3 p.Ala173Thr Uncertain significance ★ ⚠ same type
ECHDC3 p.Ala36Gly Uncertain significance ★ ⚠ same type
ECHDC3 p.Arg118His Uncertain significance ★ ⚠ same type
ECHDC3 p.Arg29Cys Uncertain significance ★ ⚠ same type
ECHDC3 p.Arg29His Uncertain significance ★ ⚠ same type
ECHDC3 p.Arg51Gly Uncertain significance ★ ⚠ same type
ECHDC3 p.Arg51Trp Uncertain significance ★ ⚠ same type
ECHDC3 p.Arg8Gln 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/echdc3-p-val140ile (accessed [today's date]).

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