Is SUN5 p.Pro374Ser (c.1120C>T) pathogenic?

SUN5 p.Pro374Ser (c.1120C>T) is classified Uncertain significance in SUN5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-01). AlphaMissense: likely benign (0.0731); Ultra-rare (popmax 0.0506%, mid).

How common is SUN5 p.Pro374Ser (c.1120C>T) in the general population?

SUN5 p.Pro374Ser (c.1120C>T) is ultra-rare (popmax 0.0506%, mid) (gnomAD).

What do computational predictors say about SUN5 p.Pro374Ser (c.1120C>T)?

AlphaMissense predicts likely benign (score 0.0731) — an in-silico prediction, not a clinical call.

SUN5 p.Pro374Ser

c.1120C>T · VCV3451322

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0731 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0506%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0731	likely benign
REVEL	0.047	moderately benign-leaning
SaProt	LLR -5.95	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP -1.1, phastCons 0.15
Regional constraint	o/e 0.90	unconstrained · MANE · 21 kb · p 0.021 · regional, not allelic
Overall
CADD	16.3	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 0.0506% Middle Eastern · 3/5,930 alleles

Filtering AF 0.0137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00734%

Overall 0.00533% 83/1,557,810 alleles · ultra-rare exomes 69/1,405,590 · genomes 14/152,220 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0506%	1,977
Ashkenazi Jewishnot grpmax-eligible	0.0319%	3,132
Admixed American	0.00568%	17,591
European (non-Finnish)	0.00539%	18,564
Remaining individualsnot grpmax-eligible	0.00499%	20,038
South Asian	0.0037%	27,049

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.Pro374Ser
Coding: c.1120C>T
MANE Select: NM_080675
Type: single nucleotide variant
Location: chr20:32983814 (GRCh38)
Gene constraint: LOEUF 1.146 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.31
Residue 374: 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)

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

Similar variants

SUN5 p.Arg356Cys Likely pathogenic ★★ same type
SUN5 p.Arg149Ter Likely pathogenic ★ same type
SUN5 c.984+8C>T Uncertain significance ★ same type
SUN5 p.Ala206= Uncertain significance ★ same type
SUN5 p.Ala28Ser Uncertain significance ★ ⚠ same type
SUN5 p.Ala364Ser Uncertain significance ★ ⚠ same type
SUN5 p.Ala59Thr Uncertain significance ★ ⚠ same type
SUN5 p.Ala84Val 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-pro374ser (accessed [today's date]).

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