Is ECHDC2 p.Leu227Pro (c.680T>C) pathogenic?

ECHDC2 p.Leu227Pro (c.680T>C) is classified Uncertain significance in ECHDC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-01). AlphaMissense: likely pathogenic (0.9518); Ultra-rare (popmax 0.0577%, nfe).

How common is ECHDC2 p.Leu227Pro (c.680T>C) in the general population?

ECHDC2 p.Leu227Pro (c.680T>C) is ultra-rare (popmax 0.0577%, nfe) (gnomAD).

What do computational predictors say about ECHDC2 p.Leu227Pro (c.680T>C)?

AlphaMissense predicts likely pathogenic (score 0.9518) — an in-silico prediction, not a clinical call.

ECHDC2 p.Leu227Pro

c.680T>C · rs149630672 · VCV2343423

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9518 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0577%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9518	likely pathogenic
REVEL	0.843	moderately pathogenic-leaning
SaProt	LLR -17.01	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 11	GERP 2.7, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 25 kb · p 0.66 · 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

Grpmax group 0.0577% European (non-Finnish) · 679/1,176,458 alleles

Filtering AF 0.054% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0526%

Overall 0.0465% 746/1,605,736 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0869%	1,151
European (non-Finnish)grpmax	0.0577%	1,733
African / African-American	0.00935%	10,695
Admixed American	0.00671%	14,892
Ashkenazi Jewishnot grpmax-eligible	0.00342%	29,214
Finnishnot grpmax-eligible	0.00163%	61,370

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Leu227Pro
Coding: c.680T>C
MANE Select: NM_001198961
dbSNP: rs149630672
Type: single nucleotide variant
Location: chr1:52904668 (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-leu227pro (accessed [today's date]).

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