Is SIM1 p.Thr653= (c.1959C>T) pathogenic?

SIM1 p.Thr653= (c.1959C>T) is classified Benign/Likely benign in SIM1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-29). Low-frequency (popmax 2.32%, nfe); Associated with obesity due to SIM1 deficiency.

What condition is associated with SIM1 p.Thr653= (c.1959C>T)?

SIM1 p.Thr653= (c.1959C>T) is associated with obesity due to SIM1 deficiency (ClinVar).

How common is SIM1 p.Thr653= (c.1959C>T) in the general population?

SIM1 p.Thr653= (c.1959C>T) is low-frequency (popmax 2.32%, nfe) (gnomAD).

SIM1 p.Thr653=

c.1959C>T · rs41318041 · VCV904718

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.32%, nfe)

Conditions

obesity due to SIM1 deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.34	GERP -4.9, phastCons 0.001
Overall
CADD	5.94	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.32% European (non-Finnish) · 27,389/1,179,990 alleles

Filtering AF 2.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.29%

Overall 1.94% 31,291/1,614,074 alleles · low-frequency exomes 29,076/1,461,850 · genomes 2,215/152,224 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	5.59%	18
European (non-Finnish)grpmax	2.32%	43
Finnishnot grpmax-eligible	2.02%	50
Remaining individualsnot grpmax-eligible	1.84%	54
Ashkenazi Jewishnot grpmax-eligible	0.801%	125
Admixed American	0.787%	127
South Asian	0.476%	210
Middle Eastern	0.33%	303
African / African-American	0.319%	314
East Asian	0.00891%	11,219

Amish 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: SIM1
Protein: p.Thr653=
Coding: c.1959C>T
MANE Select: NM_005068
dbSNP: rs41318041
Type: single nucleotide variant
Location: chr6:100390703 (GRCh38)
Gene constraint: LOEUF 0.332 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 60.70
Residue 653: the single-minded c-terminal domain

Full SIM1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

obesity due to SIM1 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SIM1 p.Gln704Leu Uncertain significance ★★ ⚠ same condition
SIM1 p.Leu332Phe Uncertain significance ★★ ⚠ same condition
SIM1 p.Ser622Phe Uncertain significance ★★ ⚠ same condition
SIM1 p.Ser680Leu Uncertain significance ★★ ⚠ same condition
SIM1 p.Val76Ile Uncertain significance ★★ ⚠ same condition
SIM1 c.544-15A>C Benign ★★ same condition
SIM1 p.Ala371Val Benign ★★ same condition
SIM1 p.Arg665His Benign ★★ 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/sim1-p-thr653 (accessed [today's date]).

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