Is ECM2 p.Arg570Trp (c.1708C>T) pathogenic?

ECM2 p.Arg570Trp (c.1708C>T) is classified Uncertain significance in ECM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-30). AlphaMissense: likely benign (0.2207); Ultra-rare (popmax 0.0145%, nfe).

How common is ECM2 p.Arg570Trp (c.1708C>T) in the general population?

ECM2 p.Arg570Trp (c.1708C>T) is ultra-rare (popmax 0.0145%, nfe) (gnomAD).

What do computational predictors say about ECM2 p.Arg570Trp (c.1708C>T)?

AlphaMissense predicts likely benign (score 0.2207) — an in-silico prediction, not a clinical call.

ECM2 p.Arg570Trp

c.1708C>T · rs199600306 · VCV2467278

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2207 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0145%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2207	likely benign
REVEL	0.217	benign-leaning
SaProt	LLR -9.79	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 7.6	GERP 2.5, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 27 kb · p 0.0043 · regional, not allelic
Overall
CADD	29.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0145% European (non-Finnish) · 171/1,180,048 alleles

Filtering AF 0.0127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.012%

Overall 0.0121% 195/1,614,032 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0145%	6,901
Remaining individualsnot grpmax-eligible	0.0144%	6,943
South Asian	0.00988%	10,120
African / African-American	0.00801%	12,484

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.Arg570Trp
Coding: c.1708C>T
MANE Select: NM_001393
dbSNP: rs199600306
Type: single nucleotide variant
Location: chr9:92500950 (GRCh38)
Gene constraint: LOEUF 1.003 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.96

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

Similar variants

ECM2 p.Arg315Leu Uncertain significance ★ ⚠ same type
ECM2 p.Asn653Ser Uncertain significance ★ ⚠ same type
ECM2 p.Gln194Glu Uncertain significance ★ ⚠ same type
ECM2 p.Glu278Lys Uncertain significance ★ ⚠ same type
ECM2 p.Ile643Met Uncertain significance ★ same type
ECM2 p.Leu306Val Uncertain significance ★ ⚠ same type
ECM2 p.Leu372Pro Uncertain significance ★ ⚠ same type
ECM2 p.Pro386Leu 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/ecm2-p-arg570trp (accessed [today's date]).

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