Is ECM2 p.Ser354Pro (c.1060T>C) pathogenic?

ECM2 p.Ser354Pro (c.1060T>C) is classified Uncertain significance in ECM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-20). AlphaMissense: ambiguous (0.3511); Ultra-rare (popmax 0.0478%, nfe).

How common is ECM2 p.Ser354Pro (c.1060T>C) in the general population?

ECM2 p.Ser354Pro (c.1060T>C) is ultra-rare (popmax 0.0478%, nfe) (gnomAD).

What do computational predictors say about ECM2 p.Ser354Pro (c.1060T>C)?

AlphaMissense predicts ambiguous (score 0.3511) — an in-silico prediction, not a clinical call.

ECM2 p.Ser354Pro

c.1060T>C · rs141793116 · VCV2456420

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3511 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0478%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3511	ambiguous
REVEL	0.177	moderately benign-leaning
SaProt	LLR -11.93	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 2.3	GERP -1.3, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 27 kb · p 0.0043 · regional, not allelic
Overall
CADD	22.5	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 0.0478% European (non-Finnish) · 563/1,178,218 alleles

Filtering AF 0.0445% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0432%

Overall 0.0372% 599/1,611,910 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0478%	2,093
Middle Eastern	0.0329%	3,040
Finnishnot grpmax-eligible	0.0312%	3,201
Remaining individualsnot grpmax-eligible	0.0144%	6,931
Admixed American	0.00667%	14,995
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,568

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.Ser354Pro
Coding: c.1060T>C
MANE Select: NM_001012267 · reported on NM_001393
dbSNP: rs141793116
Type: single nucleotide variant
Location: chr9:92512121 (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-ser354pro (accessed [today's date]).

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