Is MERTK p.Arg466Lys (c.1397G>A) pathogenic?

MERTK p.Arg466Lys (c.1397G>A) is classified Benign in MERTK (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0615); Common (popmax 65.8%, afr) — too common for a highly-penetrant pathogenic allele; Associated with inherited retinal dystrophy.

What condition is associated with MERTK p.Arg466Lys (c.1397G>A)?

MERTK p.Arg466Lys (c.1397G>A) is associated with inherited retinal dystrophy, retinitis pigmentosa 38, retinitis pigmentosa (ClinVar).

What do computational predictors say about MERTK p.Arg466Lys (c.1397G>A)?

AlphaMissense predicts likely benign (score 0.0615) — an in-silico prediction, not a clinical call.

MERTK p.Arg466Lys

Q: How common is MERTK p.Arg466Lys (c.1397G>A) in the general population?

MERTK p.Arg466Lys (c.1397G>A) is common (popmax 65.8%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1397G>A · rs7604639 · VCV330754

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0615 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 65.8%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.0615	likely benign
REVEL	0.046	moderately benign-leaning
SaProt	LLR -6.72	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 -1.8	GERP -3.4
Regional constraint	o/e 0.90	unconstrained · MANE · 130 kb · p 0.00043 · regional, not allelic
Overall
CADD	0.006	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 65.8% African / African-American · 49,292/74,930 alleles

Filtering AF 65.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 65.1%

Overall 61.3% 988,789/1,613,772 alleles · common

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	66.8%	1
African / African-Americangrpmax	65.8%	2
Ashkenazi Jewishnot grpmax-eligible	63.6%	2
Admixed American	63.3%	2
Middle Eastern	63%	2
European (non-Finnish)	62.1%	2
Remaining individualsnot grpmax-eligible	61.3%	2
South Asian	58.5%	2
Amishnot grpmax-eligible	49.9%	2
East Asian	24.3%	4

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.Arg466Lys
Coding: c.1397G>A
MANE Select: NM_006343
dbSNP: rs7604639
Type: single nucleotide variant
Location: chr2:111994351 (GRCh38)
Gene constraint: LOEUF 0.787 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.78 · 42 PDB
Residue 466: a UniProt-annotated variant site (in); a β-strand; the fibronectin type-iii 2 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 38 retinitis pigmentosa

Similar variants

MERTK p.Arg466Gly Conflicting classifications of pathogenicity ★ ⚠ 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-arg466lys (accessed [today's date]).

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