Is MERTK p.Arg445Gln (c.1334G>A) pathogenic?

MERTK p.Arg445Gln (c.1334G>A) is classified Uncertain significance in MERTK (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-10-01). AlphaMissense: likely benign (0.0673); Ultra-rare (popmax 0.0201%, eas); Associated with inherited retinal dystrophy.

What condition is associated with MERTK p.Arg445Gln (c.1334G>A)?

MERTK p.Arg445Gln (c.1334G>A) is associated with inherited retinal dystrophy (ClinVar).

How common is MERTK p.Arg445Gln (c.1334G>A) in the general population?

MERTK p.Arg445Gln (c.1334G>A) is ultra-rare (popmax 0.0201%, eas) (gnomAD).

What do computational predictors say about MERTK p.Arg445Gln (c.1334G>A)?

AlphaMissense predicts likely benign (score 0.0673) — an in-silico prediction, not a clinical call.

MERTK p.Arg445Gln

c.1334G>A · rs202242962 · VCV961387

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0673 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0201%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.0673	likely benign
REVEL	0.02	moderately benign-leaning
SaProt	LLR -4.78	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 -7.4	GERP -3.2
Regional constraint	o/e 0.90	unconstrained · MANE · 130 kb · p 0.00043 · regional, not allelic
Overall
CADD	0.003	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0201% East Asian · 9/44,874 alleles

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

Overall 0.00273% 44/1,614,128 alleles · ultra-rare exomes 34/1,461,846 · genomes 10/152,282 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0201%	4,986
African / African-American	0.016%	6,253
South Asian	0.00549%	18,214
Remaining individualsnot grpmax-eligible	0.0032%	31,255
European (non-Finnish)	0.00136%	73,752

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.Arg445Gln
Coding: c.1334G>A
MANE Select: NM_006343
dbSNP: rs202242962
Type: single nucleotide variant
Location: chr2:111994288 (GRCh38)
Gene constraint: LOEUF 0.787 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.78 · 42 PDB
Residue 445: 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

Similar variants

MERTK p.Arg445Ter Pathogenic ★ same residue
MERTK c.2189+1G>T Pathogenic ★★ same condition
MERTK p.Ala768Thr Pathogenic/Likely pathogenic ★★ same condition
MERTK p.Arg651Ter Pathogenic ★★ same condition
MERTK p.Arg722Ter Pathogenic ★★ same condition
MERTK p.Arg727Ter Pathogenic ★★ same condition
MERTK p.Arg732Ter Pathogenic ★★ same condition
MERTK p.Arg775Ter 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-arg445gln (accessed [today's date]).

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