Is MERTK p.His694Arg (c.2081A>G) pathogenic?

MERTK p.His694Arg (c.2081A>G) is classified Uncertain significance in MERTK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-01). AlphaMissense: likely benign (0.0914); Very rare (popmax 8.53e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with MERTK p.His694Arg (c.2081A>G)?

MERTK p.His694Arg (c.2081A>G) is associated with Inborn genetic diseases, retinitis pigmentosa (ClinVar).

How common is MERTK p.His694Arg (c.2081A>G) in the general population?

MERTK p.His694Arg (c.2081A>G) is very rare (popmax 8.53e-05%, nfe) (gnomAD).

What do computational predictors say about MERTK p.His694Arg (c.2081A>G)?

AlphaMissense predicts likely benign (score 0.0914) — an in-silico prediction, not a clinical call.

MERTK p.His694Arg

c.2081A>G · rs886054759 · VCV330767

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0914 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.53e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0914	likely benign
REVEL	0.251	benign-leaning
SaProt	LLR -4.25	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 4.4	GERP 0.71, phastCons 0.96
Regional constraint	o/e 0.90	unconstrained · MANE · 130 kb · p 0.00043 · regional, not allelic
Overall
CADD	21.3	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 8.53e-05% European (non-Finnish) · 1/1,172,906 alleles

Overall 6.88e-05% 1/1,454,030 alleles · very rare

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.His694Arg
Coding: c.2081A>G
MANE Select: NM_006343
dbSNP: rs886054759
Type: single nucleotide variant
Location: chr2:112019414 (GRCh38)
Gene constraint: LOEUF 0.787 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.78 · 42 PDB
Residue 694: an α-helix; the protein kinase domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: retinitis pigmentosa

Similar variants

MERTK p.His694Asp 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.Cys115Trp Pathogenic/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-his694arg (accessed [today's date]).

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