Is MERTK p.Arg865Trp (c.2593C>T) pathogenic?

MERTK p.Arg865Trp (c.2593C>T) is classified Conflicting classifications of pathogenicity in MERTK (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0848); Rare (popmax 0.237%, nfe); Associated with retinitis pigmentosa.

What condition is associated with MERTK p.Arg865Trp (c.2593C>T)?

MERTK p.Arg865Trp (c.2593C>T) is associated with retinitis pigmentosa, retinitis pigmentosa 38 (ClinVar).

How common is MERTK p.Arg865Trp (c.2593C>T) in the general population?

MERTK p.Arg865Trp (c.2593C>T) is rare (popmax 0.237%, nfe) (gnomAD).

How is Retinitis pigmentosa inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about MERTK p.Arg865Trp (c.2593C>T)?

AlphaMissense predicts likely benign (score 0.0848) — an in-silico prediction, not a clinical call.

MERTK p.Arg865Trp

c.2593C>T · rs2230516 · VCV194960

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.0848 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.237%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

retinitis pigmentosa

Computational evidence

Protein change
AlphaMissense	0.0848	likely benign
REVEL	0.115	moderately benign-leaning
SaProt	LLR -9.20	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 2.4	GERP -0.32, phastCons 0.94
Regional constraint	o/e 0.90	unconstrained · MANE · 130 kb · p 0.00043 · regional, not allelic
Overall
CADD	19.34	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 0.237% European (non-Finnish) · 2,797/1,180,042 alleles

Filtering AF 0.23% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.227%

Overall 0.215% 3,474/1,614,190 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.637%	157
European (non-Finnish)grpmax	0.237%	422
Remaining individualsnot grpmax-eligible	0.176%	568
Admixed American	0.0833%	1,201
South Asian	0.079%	1,265
Middle Eastern	0.066%	1,516
African / African-American	0.0413%	2,421
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
East Asian	0.00223%	44,892

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg865Trp
Coding: c.2593C>T
MANE Select: NM_006343
dbSNP: rs2230516
Type: single nucleotide variant
Location: chr2:112028457 (GRCh38)
Gene constraint: LOEUF 0.787 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.78 · 42 PDB
Residue 865: a UniProt-annotated variant site (in)

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

Disease context

retinitis pigmentosa — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: retinitis pigmentosa 38

For Retinitis pigmentosa (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Mitochondrial inheritance
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

MERTK p.Arg865Gln Uncertain significance ★★ ⚠ same residue
MERTK c.1296+1G>A Pathogenic/Likely pathogenic ★★ same condition
MERTK c.1605-2A>G Pathogenic ★★ same condition
MERTK c.1867+1G>A Likely pathogenic ★★ same condition
MERTK c.1868-1G>A 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

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-arg865trp (accessed [today's date]).

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