Is SUN5 p.Val261Met (c.781G>A) pathogenic?

SUN5 p.Val261Met (c.781G>A) is classified Pathogenic in SUN5 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2016-11-07). AlphaMissense: likely pathogenic (0.8266); Very rare (popmax 0.00223%, eas); Associated with spermatogenic failure 16.

What condition is associated with SUN5 p.Val261Met (c.781G>A)?

SUN5 p.Val261Met (c.781G>A) is associated with spermatogenic failure 16 (ClinVar).

How common is SUN5 p.Val261Met (c.781G>A) in the general population?

SUN5 p.Val261Met (c.781G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about SUN5 p.Val261Met (c.781G>A)?

AlphaMissense predicts likely pathogenic (score 0.8266) — an in-silico prediction, not a clinical call.

SUN5 p.Val261Met

c.781G>A · rs886041024 · VCV268051

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8266 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

spermatogenic failure 16

Computational evidence

Protein change
AlphaMissense	0.8266	likely pathogenic ✓ concordant with ClinVar
REVEL	0.625	indeterminate
SaProt	LLR -12.88	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.6, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 21 kb · p 0.021 · regional, not allelic
Overall
CADD	26.9	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 0.00223% East Asian · 1/44,884 alleles

Overall 6.2e-05% 1/1,614,132 alleles · very rare exomes 1/1,461,824 · genomes 0/152,308 · joint denominator

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.Val261Met
Coding: c.781G>A
MANE Select: NM_080675
dbSNP: rs886041024
Type: single nucleotide variant
Location: chr20:32985852 (GRCh38)
Gene constraint: LOEUF 1.146 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.31
Residue 261: a UniProt-annotated variant site (in spgf16; in mouse model abolishes interaction with dnajb13); a UniProt-annotated variant site (in spgf16; uncertain significance; in mouse model decreases protein solubility as well as 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.Arg356Cys Likely pathogenic ★★ same condition
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.Val128fs Pathogenic/Likely pathogenic ★★ same condition
SUN5 c.211+1_211+2dupGT Likely pathogenic ★ same condition
SUN5 c.984+8C>T Uncertain significance ★ 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/sun5-p-val261met (accessed [today's date]).

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