Is ECE1 p.Thr341Ile (c.1022C>T) pathogenic?

ECE1 p.Thr341Ile (c.1022C>T) is classified Benign in ECE1 (ClinVar, Multiple submitters, 2 submitters). AlphaMissense: likely benign (0.0977); Common (popmax 8.25%, nfe) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about ECE1 p.Thr341Ile (c.1022C>T)?

AlphaMissense predicts likely benign (score 0.0977) — an in-silico prediction, not a clinical call.

ECE1 p.Thr341Ile

Q: How common is ECE1 p.Thr341Ile (c.1022C>T) in the general population?

ECE1 p.Thr341Ile (c.1022C>T) is common (popmax 8.25%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1022C>T · rs1076669 · VCV258079

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0977 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 8.25%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0977	likely benign
REVEL	0.136	moderately benign-leaning
SaProt	LLR -8.57	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 5.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 11 kb · p 3.1e-08 · regional, not allelic
Overall
CADD	23.1	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 8.25% European (non-Finnish) · 97,314/1,180,002 alleles

Filtering AF 8.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 8.19%

Overall 7.11% 114,729/1,614,150 alleles · common

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	8.25%	12
Finnishnot grpmax-eligible	7.97%	13
Remaining individualsnot grpmax-eligible	6.5%	15
Middle Eastern	5.1%	20
Ashkenazi Jewishnot grpmax-eligible	4.92%	20
South Asian	4.13%	24
Amishnot grpmax-eligible	3.19%	31
Admixed American	2.92%	34
African / African-American	1.25%	80
East Asian	0.0111%	8,978

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: ECE1
Protein: p.Thr341Ile
Coding: c.1022C>T
MANE Select: NM_001397
dbSNP: rs1076669
Type: single nucleotide variant
Location: chr1:21247362 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 91.16 · 1 PDB
Residue 341: a disulfide bond; a UniProt-annotated variant site (in); the peptidase m13 domain; an α-helix

Full ECE1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ECE1 p.Thr312Met Uncertain significance ★★ ⚠ same type
ECE1 c.1020+15G>A Benign ★★ same type
ECE1 c.1164-5C>T Benign ★★ same type
ECE1 c.1278+7C>T Benign ★★ same type
ECE1 c.1782-4C>A Benign ★★ same type
ECE1 c.828+8T>C Benign ★★ same type
ECE1 p.Asn397Ser Benign ★★ same type
ECE1 p.Asp547= Benign ★★ 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/ece1-p-thr341ile (accessed [today's date]).

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