Is MERTK p.Arg755Cys (c.2263C>T) pathogenic?

MERTK p.Arg755Cys (c.2263C>T) is classified Uncertain significance in MERTK (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-16). AlphaMissense: likely pathogenic (0.7424); Ultra-rare (popmax 0.0165%, mid).

How common is MERTK p.Arg755Cys (c.2263C>T) in the general population?

MERTK p.Arg755Cys (c.2263C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about MERTK p.Arg755Cys (c.2263C>T)?

AlphaMissense predicts likely pathogenic (score 0.7424) — an in-silico prediction, not a clinical call.

MERTK p.Arg755Cys

c.2263C>T · rs766586677 · VCV1922687

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7424 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7424	likely pathogenic
REVEL	0.834	moderately pathogenic-leaning
SaProt	LLR -13.87	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 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 130 kb · p 0.00043 · regional, not allelic
Overall
CADD	34.0	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 0.0165% Middle Eastern · 1/6,072 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.00105% 17/1,613,738 alleles · ultra-rare exomes 16/1,461,676 · genomes 1/152,062 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,072
African / African-American	0.00267%	37,430
East Asian	0.00223%	44,896
Remaining individualsnot grpmax-eligible	0.0016%	62,466
European (non-Finnish)	0.00102%	98,323

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.Arg755Cys
Coding: c.2263C>T
MANE Select: NM_006343
dbSNP: rs766586677
Type: single nucleotide variant
Location: chr2:112021495 (GRCh38)
Gene constraint: LOEUF 0.787 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.78 · 42 PDB
Residue 755: the protein kinase domain; an α-helix

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

Similar variants

MERTK p.Arg755His Uncertain significance ★★ ⚠ same residue
MERTK p.Arg755fs Pathogenic/Likely pathogenic ★★ same residue
MERTK c.1296+1G>A Pathogenic/Likely pathogenic ★★ same type
MERTK c.1605-2A>G Pathogenic ★★ same type
MERTK c.1787-2A>T Pathogenic/Likely pathogenic ★★ same type
MERTK c.1867+1G>A Likely pathogenic ★★ same type
MERTK c.1868-1G>A Pathogenic ★★ same type
MERTK c.2189+1G>T Pathogenic ★★ 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/mertk-p-arg755cys (accessed [today's date]).

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