Is SIM1 p.Gly700= (c.2100C>G) pathogenic?

SIM1 p.Gly700= (c.2100C>G) is classified Benign/Likely benign in SIM1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-17). Low-frequency (popmax 1.02%, afr); Associated with obesity due to SIM1 deficiency.

What condition is associated with SIM1 p.Gly700= (c.2100C>G)?

SIM1 p.Gly700= (c.2100C>G) is associated with obesity due to SIM1 deficiency (ClinVar).

How common is SIM1 p.Gly700= (c.2100C>G) in the general population?

SIM1 p.Gly700= (c.2100C>G) is low-frequency (popmax 1.02%, afr) (gnomAD).

SIM1 p.Gly700=

c.2100C>G · rs77655804 · VCV728950

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.02%, afr)

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 2.5	GERP 0.71, phastCons 1
Overall
CADD	6.325	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.02% African / African-American · 768/75,048 alleles

Filtering AF 0.963% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.939%

Overall 0.055% 888/1,614,176 alleles · low-frequency exomes 421/1,461,878 · genomes 467/152,298 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.02%	98
Admixed American	0.1%	1,000
Remaining individualsnot grpmax-eligible	0.0784%	1,276
Middle Eastern	0.0165%	6,062
European (non-Finnish)	0.000847%	118,003

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.Gly700=
Coding: c.2100C>G
MANE Select: NM_005068
dbSNP: rs77655804
Type: single nucleotide variant
Location: chr6:100390562 (GRCh38)
Gene constraint: LOEUF 0.332 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 60.70
Residue 700: 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-gly700 (accessed [today's date]).

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