What do computational predictors say about ECH1 p.Glu41Ala (c.122A>C)?

AlphaMissense predicts likely benign (score 0.0627) — an in-silico prediction, not a clinical call.

ECH1 p.Glu41Ala

Q: Is ECH1 p.Glu41Ala (c.122A>C) pathogenic?

ECH1 p.Glu41Ala (c.122A>C) is classified Benign in ECH1 (ClinVar, Single submitter, 2 submitters). AlphaMissense: likely benign (0.0627); Common (popmax 56.3%, nfe) — too common for a highly-penetrant pathogenic allele.

Q: How common is ECH1 p.Glu41Ala (c.122A>C) in the general population?

ECH1 p.Glu41Ala (c.122A>C) is common (popmax 56.3%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.122A>C · rs9419 · VCV559115

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0627 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 56.3%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0627	likely benign
REVEL	0.037	moderately benign-leaning
SaProt	LLR -5.44	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.71	GERP 0.52
Regional constraint	o/e 1.03	unconstrained · MANE · 16 kb · p 0.49 · regional, not allelic
Overall
CADD	9.328	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 56.3% European (non-Finnish) · 664,798/1,179,818 alleles

Filtering AF 56.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 56.2%

Overall 52.3% 844,211/1,613,542 alleles · common

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	56.3%	2
Amishnot grpmax-eligible	54.1%	2
Finnishnot grpmax-eligible	53.9%	2
Middle Eastern	50.3%	2
Remaining individualsnot grpmax-eligible	50.3%	2
South Asian	45.9%	2
Ashkenazi Jewishnot grpmax-eligible	45.8%	2
Admixed American	40.6%	2
East Asian	26.5%	4
African / African-American	24.7%	4

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: ECH1
Protein: p.Glu41Ala
Coding: c.122A>C
MANE Select: NM_001398
dbSNP: rs9419
Type: single nucleotide variant
Location: chr19:38831447 (GRCh38)
Gene constraint: LOEUF 1.083 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.61 · 2 PDB
Residue 41: a UniProt-annotated variant site (in)

Full ECH1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

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ECH1 p.Ala226Thr Uncertain significance ★ ⚠ same type
ECH1 p.Ala237Val Uncertain significance ★ ⚠ same type
ECH1 p.Ala259Thr Uncertain significance ★ ⚠ same type
ECH1 p.Ala3Thr Uncertain significance ★ ⚠ same type
ECH1 p.Ala50Thr Uncertain significance ★ ⚠ same type
ECH1 p.Arg137Trp Uncertain significance ★ ⚠ same type
ECH1 p.Arg143His 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/ech1-p-glu41ala (accessed [today's date]).

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