Is ECHDC2 p.Ala152Thr (c.454G>A) pathogenic?

ECHDC2 p.Ala152Thr (c.454G>A) is classified Uncertain significance in ECHDC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-19). AlphaMissense: ambiguous (0.4157); Ultra-rare (popmax 0.0354%, sas).

How common is ECHDC2 p.Ala152Thr (c.454G>A) in the general population?

ECHDC2 p.Ala152Thr (c.454G>A) is ultra-rare (popmax 0.0354%, sas) (gnomAD).

What do computational predictors say about ECHDC2 p.Ala152Thr (c.454G>A)?

AlphaMissense predicts ambiguous (score 0.4157) — an in-silico prediction, not a clinical call.

ECHDC2 p.Ala152Thr

c.454G>A · VCV4662910

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4157 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0354%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4157	ambiguous
REVEL	0.808	moderately pathogenic-leaning
SaProt	LLR -9.69	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 25 kb · p 0.66 · regional, not allelic
Overall
CADD	26.1	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 0.0354% South Asian · 32/90,346 alleles

Filtering AF 0.0258% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0224%

Overall 0.00224% 36/1,610,578 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0354%	2,823
Remaining individualsnot grpmax-eligible	0.00642%	15,587

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.Ala152Thr
Coding: c.454G>A
MANE Select: NM_001198961
Type: single nucleotide variant
Location: chr1:52906522 (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.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
ECHDC2 p.Ala220Thr 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-ala152thr (accessed [today's date]).

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