Is SUN2 p.Glu653Lys (c.1957G>A) pathogenic?

SUN2 p.Glu653Lys (c.1957G>A) is classified Uncertain significance in SUN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-30). AlphaMissense: likely benign (0.117); Very rare (popmax 0.00267%, afr).

How common is SUN2 p.Glu653Lys (c.1957G>A) in the general population?

SUN2 p.Glu653Lys (c.1957G>A) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about SUN2 p.Glu653Lys (c.1957G>A)?

AlphaMissense predicts likely benign (score 0.117) — an in-silico prediction, not a clinical call.

SUN2 p.Glu653Lys

c.1957G>A · rs749813392 · VCV2247242

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.117 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

⚠ 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	0.117	likely benign
REVEL	0.115	moderately benign-leaning
SaProt	LLR -9.07	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 5.8	GERP -1, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 2,037 bp · p 3.5e-07 · regional, not allelic
Overall
CADD	33.0	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 0.00267% African / African-American · 2/75,020 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000558% 9/1,613,656 alleles · very rare exomes 9/1,461,434 · genomes 0/152,222 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,510
East Asian	0.00223%	44,868
Admixed American	0.00167%	60,010
European (non-Finnish)	0.000424%	235,970

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.Glu653Lys
Coding: c.1957G>A
MANE Select: NM_015374
dbSNP: rs749813392
Type: single nucleotide variant
Location: chr22:38738256 (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-glu653lys (accessed [today's date]).

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