Is ECM2 p.Thr501Ile (c.1502C>T) pathogenic?

ECM2 p.Thr501Ile (c.1502C>T) is classified Uncertain significance in ECM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-13). AlphaMissense: ambiguous (0.5042); Very rare (popmax 0.00509%, amr).

How common is ECM2 p.Thr501Ile (c.1502C>T) in the general population?

ECM2 p.Thr501Ile (c.1502C>T) is very rare (popmax 0.00509%, amr) (gnomAD).

What do computational predictors say about ECM2 p.Thr501Ile (c.1502C>T)?

AlphaMissense predicts ambiguous (score 0.5042) — an in-silico prediction, not a clinical call.

ECM2 p.Thr501Ile

c.1502C>T · rs1394575979 · VCV3086989

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5042 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00509%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5042	ambiguous
REVEL	0.065	moderately benign-leaning
SaProt	LLR -10.67	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 4.8	GERP -0.021, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 27 kb · p 0.0043 · 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 0.00509% Admixed American · 3/58,972 alleles

Filtering AF 0.00135% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000674%

Overall 0.000375% 6/1,601,670 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00509%	19,657
East Asian	0.00224%	44,722
Remaining individualsnot grpmax-eligible	0.00161%	62,070
African / African-American	0.00134%	74,586

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.Thr501Ile
Coding: c.1502C>T
MANE Select: NM_001012267 · reported on NM_001393
dbSNP: rs1394575979
Type: single nucleotide variant
Location: chr9:92502615 (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-thr501ile (accessed [today's date]).

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