Is MERTK p.Leu684Pro (c.2051T>C) pathogenic?

MERTK p.Leu684Pro (c.2051T>C) is classified Uncertain significance in MERTK (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-01). AlphaMissense: likely pathogenic (0.9784); Very rare (popmax 0.00017%, nfe); Associated with inherited retinal dystrophy.

What condition is associated with MERTK p.Leu684Pro (c.2051T>C)?

MERTK p.Leu684Pro (c.2051T>C) is associated with inherited retinal dystrophy (ClinVar).

How common is MERTK p.Leu684Pro (c.2051T>C) in the general population?

MERTK p.Leu684Pro (c.2051T>C) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about MERTK p.Leu684Pro (c.2051T>C)?

AlphaMissense predicts likely pathogenic (score 0.9784) — an in-silico prediction, not a clinical call.

MERTK p.Leu684Pro

c.2051T>C · rs370309420 · VCV3028881

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9784 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.9784	likely pathogenic · top 5% in MERTK
REVEL	0.703	pathogenic-leaning
SaProt	LLR -14.98	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 130 kb · p 0.00043 · regional, not allelic
Overall
CADD	29.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00017% European (non-Finnish) · 2/1,179,140 alleles

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

Overall 0.000124% 2/1,613,044 alleles · very rare exomes 1/1,460,840 · genomes 1/152,204 · 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: MERTK
Protein: p.Leu684Pro
Coding: c.2051T>C
MANE Select: NM_006343
dbSNP: rs370309420
Type: single nucleotide variant
Location: chr2:112010038 (GRCh38)
Gene constraint: LOEUF 0.787 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.78 · 42 PDB
Residue 684: an α-helix; the protein kinase domain

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

Disease context

inherited retinal dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MERTK c.2189+1G>T Pathogenic ★★ same condition
MERTK p.Ala768Thr Pathogenic/Likely pathogenic ★★ same condition
MERTK p.Arg651Ter Pathogenic ★★ same condition
MERTK p.Arg722Ter Pathogenic ★★ same condition
MERTK p.Arg727Ter Pathogenic ★★ same condition
MERTK p.Arg732Ter Pathogenic ★★ same condition
MERTK p.Arg775Ter Pathogenic ★★ same condition
MERTK p.Arg844Cys Pathogenic ★★ 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/mertk-p-leu684pro (accessed [today's date]).

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