Is MERTK p.His680Arg (c.2039A>G) pathogenic?

MERTK p.His680Arg (c.2039A>G) is classified Uncertain significance in MERTK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-09-06). AlphaMissense: likely pathogenic (0.6303); Very rare (popmax 0.000339%, nfe); Associated with Inborn genetic diseases.

What condition is associated with MERTK p.His680Arg (c.2039A>G)?

MERTK p.His680Arg (c.2039A>G) is associated with Inborn genetic diseases (ClinVar).

How common is MERTK p.His680Arg (c.2039A>G) in the general population?

MERTK p.His680Arg (c.2039A>G) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about MERTK p.His680Arg (c.2039A>G)?

AlphaMissense predicts likely pathogenic (score 0.6303) — an in-silico prediction, not a clinical call.

MERTK p.His680Arg

c.2039A>G · rs749028235 · VCV1349982

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6303 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6303	likely pathogenic
REVEL	0.524	indeterminate
SaProt	LLR -7.77	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 130 kb · p 0.00043 · regional, not allelic
Overall
CADD	25.5	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 0.000339% European (non-Finnish) · 4/1,179,778 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00093% 15/1,613,748 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0338%	2,959
Remaining individualsnot grpmax-eligible	0.0016%	62,468
European (non-Finnish)grpmax	0.000339%	294,944

Ashkenazi Jewish 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.His680Arg
Coding: c.2039A>G
MANE Select: NM_006343
dbSNP: rs749028235
Type: single nucleotide variant
Location: chr2:112010026 (GRCh38)
Gene constraint: LOEUF 0.787 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.78 · 42 PDB
Residue 680: 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

Similar variants

MERTK p.His680Gln Uncertain significance ★★ ⚠ same residue
MERTK p.His680Pro Conflicting classifications of pathogenicity ★ ⚠ same residue
MERTK p.Ala29Gly Uncertain significance ★★ ⚠ same condition
MERTK p.Ala353Val Uncertain significance ★★ ⚠ same condition
MERTK p.Ala773Thr Uncertain significance ★★ ⚠ same condition
MERTK p.Ala944Thr Uncertain significance ★★ ⚠ same condition
MERTK p.Arg237Cys Uncertain significance ★★ ⚠ same condition
MERTK p.Arg557Gln Uncertain significance ★★ ⚠ 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-his680arg (accessed [today's date]).

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