Is ECE1 p.Arg627Trp (c.1879C>T) pathogenic?

ECE1 p.Arg627Trp (c.1879C>T) is classified Likely pathogenic in ECE1 (ClinVar, No assertion criteria, 1 submitter). AlphaMissense: ambiguous (0.3429); Very rare (popmax 0.00167%, amr); Associated with Hirschsprung disease.

What condition is associated with ECE1 p.Arg627Trp (c.1879C>T)?

ECE1 p.Arg627Trp (c.1879C>T) is associated with Hirschsprung disease (ClinVar).

How common is ECE1 p.Arg627Trp (c.1879C>T) in the general population?

ECE1 p.Arg627Trp (c.1879C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

How is Hirschsprung disease inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ECE1 p.Arg627Trp (c.1879C>T)?

AlphaMissense predicts ambiguous (score 0.3429) — an in-silico prediction, not a clinical call.

ECE1 p.Arg627Trp

c.1879C>T · rs200894751 · VCV599419

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3429 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Hirschsprung disease

Computational evidence

Protein change
AlphaMissense	0.3429	ambiguous
REVEL	0.768	pathogenic-leaning
SaProt	LLR -12.82	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 0.85, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 27 kb · p 1.3e-06 · regional, not allelic
Overall
CADD	33.0	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 0.00167% Admixed American · 1/59,996 alleles

Filtering AF 0.000688% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.00954% 154/1,614,036 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.216%	464
Admixed Americangrpmax	0.00167%	59,996
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)	0.00119%	84,288

Finnish 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: ECE1
Protein: p.Arg627Trp
Coding: c.1879C>T
MANE Select: NM_001397
dbSNP: rs200894751
Type: single nucleotide variant
Location: chr1:21225411 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 91.16 · 1 PDB
Residue 627: a disulfide bond; the peptidase m13 domain

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

Disease context

Hirschsprung disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hirschsprung disease (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Multigenic/multifactorial
Onset: Childhood, Infancy, Neonatal
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

ECE1 p.Phe356Cys Likely pathogenic same condition
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

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-arg627trp (accessed [today's date]).

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