Is EMILIN1 p.Ser656Phe (c.1967C>T) pathogenic?

EMILIN1 p.Ser656Phe (c.1967C>T) is classified Uncertain significance in EMILIN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-20). AlphaMissense: likely benign (0.3295); Very rare (popmax 0.005%, amr); Associated with Inborn genetic diseases.

What condition is associated with EMILIN1 p.Ser656Phe (c.1967C>T)?

EMILIN1 p.Ser656Phe (c.1967C>T) is associated with Inborn genetic diseases (ClinVar).

How common is EMILIN1 p.Ser656Phe (c.1967C>T) in the general population?

EMILIN1 p.Ser656Phe (c.1967C>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about EMILIN1 p.Ser656Phe (c.1967C>T)?

AlphaMissense predicts likely benign (score 0.3295) — an in-silico prediction, not a clinical call.

EMILIN1 p.Ser656Phe

c.1967C>T · VCV3508197

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3295 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3295	likely benign
REVEL	0.366	indeterminate
SaProt	LLR -8.05	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.2, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 6,946 bp · p 0.15 · regional, not allelic
Overall
CADD	26.4	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 0.005% Admixed American · 3/60,020 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000342% 5/1,461,754 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,007
African / African-American	0.00133%	75,062
South Asian	0.0011%	91,086

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: EMILIN1
Protein: p.Ser656Phe
Coding: c.1967C>T
MANE Select: NM_007046
Type: single nucleotide variant
Location: chr2:27083538 (GRCh38)
Gene constraint: LOEUF 0.832 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.73 · 2 PDB
Residue 656: a UniProt-annotated variant site (in atbfs; likely pathogenic; strong reduction of mrna levels in homozygous patient cells; loss of localization to extracellular matrix though a minor amount of mutant protein remains detectable in patient cell lysate)

Full EMILIN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EMILIN1 p.Arg107His Uncertain significance ★★ ⚠ same condition
EMILIN1 p.Arg594His Uncertain significance ★★ ⚠ same condition
EMILIN1 p.Gly374Ser Uncertain significance ★★ ⚠ same condition
EMILIN1 p.His805Arg Uncertain significance ★★ ⚠ same condition
EMILIN1 p.Ala134Thr Uncertain significance ★ ⚠ same condition
EMILIN1 p.Ala136Val Uncertain significance ★ ⚠ same condition
EMILIN1 p.Ala22Thr Uncertain significance ★ ⚠ same condition
EMILIN1 p.Ala307Pro Uncertain significance ★ ⚠ same condition

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/emilin1-p-ser656phe (accessed [today's date]).

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