Is EMILIN2 p.Cys553Phe (c.1658G>T) pathogenic?

EMILIN2 p.Cys553Phe (c.1658G>T) is classified Uncertain significance in EMILIN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-08). AlphaMissense: ambiguous (0.4078); Very rare (popmax 0.00133%, afr).

How common is EMILIN2 p.Cys553Phe (c.1658G>T) in the general population?

EMILIN2 p.Cys553Phe (c.1658G>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about EMILIN2 p.Cys553Phe (c.1658G>T)?

AlphaMissense predicts ambiguous (score 0.4078) — an in-silico prediction, not a clinical call.

EMILIN2 p.Cys553Phe

c.1658G>T · VCV4664088

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4078 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Computational evidence

Protein change
AlphaMissense	0.4078	ambiguous
REVEL	0.423	indeterminate
SaProt	LLR -7.12	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.1, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 66 kb · p 0.34 · regional, not allelic
Overall
CADD	23.2	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 0.00133% African / African-American · 1/75,044 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000205% 3/1,461,894 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,044
European (non-Finnish)	0.000169%	590,019

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: EMILIN2
Protein: p.Cys553Phe
Coding: c.1658G>T
MANE Select: NM_032048
Type: single nucleotide variant
Location: chr18:2891785 (GRCh38)
Gene constraint: LOEUF 1.047 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.88

Full EMILIN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EMILIN2 p.Ala215Thr Benign ★★ same type
EMILIN2 p.Ala455= Benign ★★ same type
EMILIN2 p.Cys1002= Benign ★★ same type
EMILIN2 p.Gly843= Benign/Likely benign ★★ same type
EMILIN2 p.Lys347= Benign ★★ same type
EMILIN2 p.Met259Val Benign ★★ same type
EMILIN2 p.Pro136Ser Benign ★★ same type
EMILIN2 p.Pro657= 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/emilin2-p-cys553phe (accessed [today's date]).

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