Is ECM2 p.Arg470Cys (c.1408C>T) pathogenic?

ECM2 p.Arg470Cys (c.1408C>T) is classified Uncertain significance in ECM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-24). AlphaMissense: ambiguous (0.4302); Very rare (popmax 0.0017%, amr).

How common is ECM2 p.Arg470Cys (c.1408C>T) in the general population?

ECM2 p.Arg470Cys (c.1408C>T) is very rare (popmax 0.0017%, amr) (gnomAD).

What do computational predictors say about ECM2 p.Arg470Cys (c.1408C>T)?

AlphaMissense predicts ambiguous (score 0.4302) — an in-silico prediction, not a clinical call.

ECM2 p.Arg470Cys

c.1408C>T · VCV4246416

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4302 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0017%, amr)

Computational evidence

Protein change
AlphaMissense	0.4302	ambiguous
REVEL	0.436	indeterminate
SaProt	LLR -10.76	damaging
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 9.9	GERP 2.8, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 27 kb · p 0.0043 · regional, not allelic
Overall
CADD	32.0	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 0.0017% Admixed American · 1/58,690 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.00354% 57/1,608,646 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.149%	671
Remaining individualsnot grpmax-eligible	0.00803%	12,460
Admixed Americangrpmax	0.0017%	58,690
European (non-Finnish)	0.000594%	168,380

Ashkenazi Jewish 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: ECM2
Protein: p.Arg470Cys
Coding: c.1408C>T
MANE Select: NM_001012267 · reported on NM_001393
Type: single nucleotide variant
Location: chr9:92505589 (GRCh38)

Full ECM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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/ecm2-p-arg470cys (accessed [today's date]).

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