Is ECHDC2 p.Ile246Thr (c.737T>C) pathogenic?

ECHDC2 p.Ile246Thr (c.737T>C) is classified Uncertain significance in ECHDC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-22). AlphaMissense: likely pathogenic (0.6877); Ultra-rare (popmax 0.0111%, eas).

How common is ECHDC2 p.Ile246Thr (c.737T>C) in the general population?

ECHDC2 p.Ile246Thr (c.737T>C) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

What do computational predictors say about ECHDC2 p.Ile246Thr (c.737T>C)?

AlphaMissense predicts likely pathogenic (score 0.6877) — an in-silico prediction, not a clinical call.

ECHDC2 p.Ile246Thr

c.737T>C · rs376328788 · VCV2387017

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6877 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6877	likely pathogenic
REVEL	0.736	pathogenic-leaning
SaProt	LLR -12.52	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 8	GERP 1.5, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 25 kb · p 0.66 · regional, not allelic
Overall
CADD	26.7	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

Grpmax group 0.0111% East Asian · 5/44,884 alleles

Filtering AF 0.00434% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.00149% 24/1,614,054 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0111%	8,977
African / African-American	0.00534%	18,726
Admixed American	0.00333%	29,999
Remaining individualsnot grpmax-eligible	0.0016%	62,488
Finnishnot grpmax-eligible	0.00156%	64,042
South Asian	0.0011%	91,088
European (non-Finnish)	0.000847%	118,005

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.Ile246Thr
Coding: c.737T>C
MANE Select: NM_001198961
dbSNP: rs376328788
Type: single nucleotide variant
Location: chr1:52899190 (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-ile246thr (accessed [today's date]).

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