Is SUN2 p.Arg543Cys (c.1627C>T) pathogenic?

SUN2 p.Arg543Cys (c.1627C>T) is classified Uncertain significance in SUN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-03). AlphaMissense: ambiguous (0.3624); Very rare (popmax 0.00329%, sas).

How common is SUN2 p.Arg543Cys (c.1627C>T) in the general population?

SUN2 p.Arg543Cys (c.1627C>T) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about SUN2 p.Arg543Cys (c.1627C>T)?

AlphaMissense predicts ambiguous (score 0.3624) — an in-silico prediction, not a clinical call.

SUN2 p.Arg543Cys

c.1627C>T · rs754873310 · VCV2493471

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3624 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

⚠ 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	0.3624	ambiguous
REVEL	0.269	benign-leaning
SaProt	LLR -11.51	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 8.5	GERP -2.6, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 2,037 bp · p 3.5e-07 · regional, not allelic
Overall
CADD	29.2	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 0.00329% South Asian · 3/91,088 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.00403% 65/1,613,026 alleles · very rare exomes 44/1,460,810 · genomes 21/152,216 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0841%	1,189
South Asiangrpmax	0.00329%	30,363
Remaining individualsnot grpmax-eligible	0.0016%	62,476
African / African-American	0.00133%	74,930
European (non-Finnish)	0.000593%	168,576

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg543Cys
Coding: c.1627C>T
MANE Select: NM_015374
dbSNP: rs754873310
Type: single nucleotide variant
Location: chr22:38739378 (GRCh38)

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

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-arg543cys (accessed [today's date]).

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