Is SUN5 p.Arg356Cys (c.1066C>T) pathogenic?

SUN5 p.Arg356Cys (c.1066C>T) is classified Likely pathogenic in SUN5 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-03-09). AlphaMissense: likely pathogenic (0.9146); Ultra-rare (popmax 0.0523%, eas); Associated with spermatogenic failure 16.

What condition is associated with SUN5 p.Arg356Cys (c.1066C>T)?

SUN5 p.Arg356Cys (c.1066C>T) is associated with spermatogenic failure 16 (ClinVar).

How common is SUN5 p.Arg356Cys (c.1066C>T) in the general population?

SUN5 p.Arg356Cys (c.1066C>T) is ultra-rare (popmax 0.0523%, eas) (gnomAD).

What do computational predictors say about SUN5 p.Arg356Cys (c.1066C>T)?

AlphaMissense predicts likely pathogenic (score 0.9146) — an in-silico prediction, not a clinical call.

SUN5 p.Arg356Cys

c.1066C>T · rs754130052 · VCV268048

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9146 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0523%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

spermatogenic failure 16

Computational evidence

Protein change
AlphaMissense	0.9146	likely pathogenic ✓ concordant with ClinVar · top 10% in SUN5
REVEL	0.921	moderately pathogenic-leaning
SaProt	LLR -14.92	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.6, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 21 kb · p 0.021 · regional, not allelic
Overall
CADD	33.0	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 0.0523% East Asian · 23/43,964 alleles

Filtering AF 0.0357% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0302%

Overall 0.00169% 27/1,600,014 alleles · ultra-rare exomes 25/1,447,714 · genomes 2/152,300 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0523%	1,911
Remaining individualsnot grpmax-eligible	0.00161%	62,028
European (non-Finnish)	0.000256%	391,025

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: SUN5
Protein: p.Arg356Cys
Coding: c.1066C>T
MANE Select: NM_080675
dbSNP: rs754130052
Type: single nucleotide variant
Location: chr20:32983868 (GRCh38)
Gene constraint: LOEUF 1.146 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.31
Residue 356: a UniProt-annotated variant site (in spgf16; in mouse model abolishes interaction with dnajb13); a UniProt-annotated variant site (in spgf16; significant reduction in protein expression; impaired localization to nuclear inner membrane; in mouse model decreases interaction with dnajb13); a UniProt-annotated variant site (in spgf16; uncertain significance; in mouse model impairs nuclear inner membrane location and decreases interaction with dnajb13); the sun domain

Full SUN5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

spermatogenic failure 16 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SUN5 p.Arg356= Likely benign same residue
SUN5 p.Arg149Ter Likely pathogenic ★ same condition
SUN5 p.Met162Lys Pathogenic ⚠ same condition
SUN5 p.Ser284Ter Pathogenic same condition
SUN5 p.Thr275Met Pathogenic same condition
SUN5 p.Val261Met Pathogenic same condition
SUN5 p.Val128fs Pathogenic/Likely pathogenic ★★ same condition
SUN5 c.211+1_211+2dupGT Likely pathogenic ★ 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/sun5-p-arg356cys (accessed [today's date]).

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