Is LEPR p.Arg573Ser (c.1717C>A) pathogenic?

LEPR p.Arg573Ser (c.1717C>A) is classified Uncertain significance in LEPR (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-09). AlphaMissense: likely pathogenic (0.6656); Very rare (popmax 0.00017%, nfe).

How common is LEPR p.Arg573Ser (c.1717C>A) in the general population?

LEPR p.Arg573Ser (c.1717C>A) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about LEPR p.Arg573Ser (c.1717C>A)?

AlphaMissense predicts likely pathogenic (score 0.6656) — an in-silico prediction, not a clinical call.

LEPR p.Arg573Ser

c.1717C>A · rs748855258 · VCV2575606

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6656 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6656	likely pathogenic · top 10% in LEPR
REVEL	0.482	indeterminate
SaProt	LLR -9.30	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.28	donor loss · deltas
Pangolin	Δ0.49	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 71 kb · p 4.1e-05 · regional, not allelic
Overall
CADD	24.4	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 0.00017% European (non-Finnish) · 2/1,179,810 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,518 alleles · very rare exomes 1/1,461,392 · genomes 1/152,126 · joint denominator

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.Arg573Ser
Coding: c.1717C>A
MANE Select: NM_002303
dbSNP: rs748855258
Type: single nucleotide variant
Location: chr1:65608866 (GRCh38)
Gene constraint: LOEUF 0.589 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 66.49 · 9 PDB
Residue 573: the fibronectin type-iii 2 domain; a β-strand

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

Similar variants

LEPR p.Arg573His Uncertain significance ⚠ same residue
LEPR c.995-2A>G Likely pathogenic ★★ same type
LEPR p.Trp31Ter Pathogenic ★★ same type
LEPR p.Ala545= Uncertain significance ★★ same type
LEPR p.Arg678Ser Uncertain significance ★★ ⚠ same type
LEPR p.Asn397Lys Uncertain significance ★★ ⚠ same type
LEPR p.Glu565Asp Uncertain significance ★★ ⚠ same type
LEPR p.Ile1085Val Uncertain significance ★★ ⚠ same type

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-arg573ser (accessed [today's date]).

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