Is MERTK p.Leu720Pro (c.2159T>C) pathogenic?

MERTK p.Leu720Pro (c.2159T>C) is classified Conflicting classifications of pathogenicity in MERTK (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-07-01). AlphaMissense: likely pathogenic (0.9867); Very rare (popmax 0.00267%, afr); Associated with MERTK-related disorder.

What condition is associated with MERTK p.Leu720Pro (c.2159T>C)?

MERTK p.Leu720Pro (c.2159T>C) is associated with MERTK-related disorder (ClinVar).

How common is MERTK p.Leu720Pro (c.2159T>C) in the general population?

MERTK p.Leu720Pro (c.2159T>C) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about MERTK p.Leu720Pro (c.2159T>C)?

AlphaMissense predicts likely pathogenic (score 0.9867) — an in-silico prediction, not a clinical call.

MERTK p.Leu720Pro

c.2159T>C · rs756205527 · VCV846255

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9867 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

MERTK-related disorder

Computational evidence

Protein change
AlphaMissense	0.9867	likely pathogenic · top 4% in MERTK
REVEL	0.872	moderately pathogenic-leaning
SaProt	LLR -12.19	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
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	32.0	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 0.00267% African / African-American · 2/74,902 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000372% 6/1,613,670 alleles · very rare exomes 3/1,461,474 · genomes 3/152,196 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,451
European (non-Finnish)	0.000339%	294,916

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.Leu720Pro
Coding: c.2159T>C
MANE Select: NM_006343
dbSNP: rs756205527
Type: single nucleotide variant
Location: chr2:112019492 (GRCh38)
Gene constraint: LOEUF 0.787 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.78 · 42 PDB
Residue 720: the protein kinase domain

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

Disease context

MERTK-related disorder

Similar variants

MERTK c.1605-2A>G Pathogenic ★★ same condition
MERTK c.1787-2A>T Pathogenic/Likely pathogenic ★★ same condition
MERTK c.2189+1G>T Pathogenic ★★ same condition
MERTK p.Ala768Thr Pathogenic/Likely pathogenic ★★ same condition
MERTK p.Ala768Val Likely pathogenic ★★ same condition
MERTK p.Arg558Ter Pathogenic/Likely pathogenic ★★ same condition
MERTK p.Arg651Ter Pathogenic ★★ same condition
MERTK p.Arg687Ter Pathogenic/Likely 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-leu720pro (accessed [today's date]).

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