Is SUN2 p.Pro458Ser (c.1372C>T) pathogenic?

SUN2 p.Pro458Ser (c.1372C>T) is classified Benign in SUN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-19). AlphaMissense: likely benign (0.2591); Low-frequency (popmax 1.23%, afr); Associated with Emery-Dreifuss muscular dystrophy.

What condition is associated with SUN2 p.Pro458Ser (c.1372C>T)?

SUN2 p.Pro458Ser (c.1372C>T) is associated with Emery-Dreifuss muscular dystrophy (ClinVar).

How common is SUN2 p.Pro458Ser (c.1372C>T) in the general population?

SUN2 p.Pro458Ser (c.1372C>T) is low-frequency (popmax 1.23%, afr) (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.Pro458Ser (c.1372C>T)?

AlphaMissense predicts likely benign (score 0.2591) — an in-silico prediction, not a clinical call.

SUN2 p.Pro458Ser

c.1372C>T · rs76681049 · VCV704252

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2591 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.23%, afr)

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	0.2591	likely benign
REVEL	0.072	moderately benign-leaning
SaProt	LLR -9.79	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 2,037 bp · p 3.5e-07 · regional, not allelic
Overall
CADD	23.9	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 1.23% African / African-American · 922/75,058 alleles

Filtering AF 1.16% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.14%

Overall 0.0612% 987/1,611,458 alleles · low-frequency exomes 465/1,459,130 · genomes 522/152,328 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.23%	81
Remaining individualsnot grpmax-eligible	0.0592%	1,689
Admixed American	0.04%	2,501
European (non-Finnish)	0.000339%	294,989

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.Pro458Ser
Coding: c.1372C>T
MANE Select: NM_015374
dbSNP: rs76681049
Type: single nucleotide variant
Location: chr22:38739928 (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-pro458ser (accessed [today's date]).

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