Is MERTK p.Arg758His (c.2273G>A) pathogenic?

MERTK p.Arg758His (c.2273G>A) is classified Uncertain significance in MERTK (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-16). AlphaMissense: likely benign (0.1818); Ultra-rare (popmax 0.0201%, eas); Associated with inherited retinal dystrophy.

What condition is associated with MERTK p.Arg758His (c.2273G>A)?

MERTK p.Arg758His (c.2273G>A) is associated with inherited retinal dystrophy, retinitis pigmentosa (ClinVar).

How common is MERTK p.Arg758His (c.2273G>A) in the general population?

MERTK p.Arg758His (c.2273G>A) is ultra-rare (popmax 0.0201%, eas) (gnomAD).

What do computational predictors say about MERTK p.Arg758His (c.2273G>A)?

AlphaMissense predicts likely benign (score 0.1818) — an in-silico prediction, not a clinical call.

MERTK p.Arg758His

c.2273G>A · rs370526555 · VCV866612

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1818 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0201%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.1818	likely benign
REVEL	0.677	pathogenic-leaning
SaProt	LLR -7.20	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 130 kb · p 0.00043 · regional, not allelic
Overall
CADD	33.0	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 0.0201% East Asian · 9/44,882 alleles

Filtering AF 0.0104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00779%

Overall 0.00167% 27/1,613,944 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0201%	4,987
Admixed American	0.00833%	12,002
Remaining individualsnot grpmax-eligible	0.0048%	20,832
Finnishnot grpmax-eligible	0.00156%	64,002
African / African-American	0.00133%	75,010
European (non-Finnish)	0.000678%	147,488

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.Arg758His
Coding: c.2273G>A
MANE Select: NM_006343
dbSNP: rs370526555
Type: single nucleotide variant
Location: chr2:112021505 (GRCh38)
Gene constraint: LOEUF 0.787 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.78 · 42 PDB
Residue 758: 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

Also linked: retinitis pigmentosa

Similar variants

MERTK p.Arg758Cys Uncertain significance ★★ ⚠ same residue
MERTK c.1296+1G>A Pathogenic/Likely pathogenic ★★ same condition
MERTK c.2189+1G>T Pathogenic ★★ same condition
MERTK p.Ala768Thr Pathogenic/Likely pathogenic ★★ same condition
MERTK p.Arg651Ter Pathogenic ★★ same condition
MERTK p.Arg687Ter Pathogenic/Likely pathogenic ★★ same condition
MERTK p.Arg722Ter Pathogenic ★★ same condition
MERTK p.Arg727Ter 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-arg758his (accessed [today's date]).

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