Is LEPR p.Ser1007Cys (c.3019A>T) pathogenic?

LEPR p.Ser1007Cys (c.3019A>T) is classified Conflicting classifications of pathogenicity in LEPR (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-01). AlphaMissense: likely benign (0.0836); Rare (popmax 0.9%, sas); Associated with monogenic diabetes.

What condition is associated with LEPR p.Ser1007Cys (c.3019A>T)?

LEPR p.Ser1007Cys (c.3019A>T) is associated with monogenic diabetes (ClinVar).

How common is LEPR p.Ser1007Cys (c.3019A>T) in the general population?

LEPR p.Ser1007Cys (c.3019A>T) is rare (popmax 0.9%, sas) (gnomAD).

What do computational predictors say about LEPR p.Ser1007Cys (c.3019A>T)?

AlphaMissense predicts likely benign (score 0.0836) — an in-silico prediction, not a clinical call.

LEPR p.Ser1007Cys

c.3019A>T · rs145651189 · VCV297999

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0836 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.9%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

monogenic diabetes

Computational evidence

Protein change
AlphaMissense	0.0836	likely benign
REVEL	0.078	moderately benign-leaning
SaProt	LLR -8.10	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 3	GERP 0.57, phastCons 0.97
Regional constraint	o/e 0.89	unconstrained · MANE · 71 kb · p 4.1e-05 · regional, not allelic
Overall
CADD	16.31	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 0.9% South Asian · 820/91,076 alleles

Filtering AF 0.849% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.829%

Overall 0.0766% 1,236/1,614,120 alleles · rare exomes 1,154/1,461,800 · genomes 82/152,320 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.9%	111
Middle Eastern	0.693%	144
Remaining individualsnot grpmax-eligible	0.149%	672
Ashkenazi Jewishnot grpmax-eligible	0.139%	722
Admixed American	0.0733%	1,364
European (non-Finnish)	0.016%	6,243
African / African-American	0.00799%	12,509
Finnishnot grpmax-eligible	0.00156%	64,032

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: LEPR
Protein: p.Ser1007Cys
Coding: c.3019A>T
MANE Select: NM_002303
dbSNP: rs145651189
Type: single nucleotide variant
Location: chr1:65636536 (GRCh38)
Gene constraint: LOEUF 0.589 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 66.49 · 9 PDB

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

Disease context

monogenic diabetes — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LEPR p.Thr699Met Benign ★★ ⚠ same condition
LEPR p.Asn431Ser Uncertain significance ★ ⚠ same condition
LEPR p.Asp124Gly Conflicting classifications of pathogenicity ★ ⚠ same condition
LEPR p.Cys352Phe Uncertain significance ★ ⚠ same condition
LEPR p.Gln380Arg Uncertain significance ★ ⚠ same condition
LEPR p.Ile900Val Conflicting classifications of pathogenicity ★ ⚠ same condition
LEPR p.Lys656Asn Uncertain significance ★ ⚠ same condition
LEPR p.Met1160Thr Conflicting classifications of pathogenicity ★ ⚠ 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/lepr-p-ser1007cys (accessed [today's date]).

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