Is SUN2 p.Thr666Ile (c.1997C>T) pathogenic?

SUN2 p.Thr666Ile (c.1997C>T) is classified Uncertain significance in SUN2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-26). AlphaMissense: likely benign (0.1292); Ultra-rare (popmax 0.0535%, eas); Associated with Emery-Dreifuss muscular dystrophy.

What condition is associated with SUN2 p.Thr666Ile (c.1997C>T)?

SUN2 p.Thr666Ile (c.1997C>T) is associated with Emery-Dreifuss muscular dystrophy (ClinVar).

How common is SUN2 p.Thr666Ile (c.1997C>T) in the general population?

SUN2 p.Thr666Ile (c.1997C>T) is ultra-rare (popmax 0.0535%, eas) (gnomAD).

How is Emery-Dreifuss muscular dystrophy inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about SUN2 p.Thr666Ile (c.1997C>T)?

AlphaMissense predicts likely benign (score 0.1292) — an in-silico prediction, not a clinical call.

SUN2 p.Thr666Ile

c.1997C>T · rs755259603 · VCV650009

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1292 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0535%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Emery-Dreifuss muscular dystrophy

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.1292	likely benign
REVEL	0.107	moderately benign-leaning
SaProt	LLR -7.13	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 8.5	GERP -1.1, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 1,960 bp · p 0.7 · regional, not allelic
Overall
CADD	24.3	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 0.0535% East Asian · 24/44,890 alleles

Filtering AF 0.0368% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0313%

Overall 0.00155% 25/1,613,888 alleles · ultra-rare exomes 22/1,461,714 · genomes 3/152,174 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0535%	1,870
African / African-American	0.00134%	74,906

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: SUN2
Protein: p.Thr666Ile
Coding: c.1997C>T
MANE Select: NM_015374
dbSNP: rs755259603
Type: single nucleotide variant
Location: chr22:38738216 (GRCh38)

Full SUN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Emery-Dreifuss muscular dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Emery-Dreifuss muscular dystrophy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Childhood
Prevalence: 1-9 / 1 000 000 (Europe)

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/sun2-p-thr666ile (accessed [today's date]).

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