Is MERTK p.His680Pro (c.2039A>C) pathogenic?

MERTK p.His680Pro (c.2039A>C) is classified Conflicting classifications of pathogenicity in MERTK (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-06-22). AlphaMissense: likely pathogenic (0.9443); Very rare (popmax 0.000339%, nfe); Associated with MERTK-related disorder.

What condition is associated with MERTK p.His680Pro (c.2039A>C)?

MERTK p.His680Pro (c.2039A>C) is associated with MERTK-related disorder (ClinVar).

How common is MERTK p.His680Pro (c.2039A>C) in the general population?

MERTK p.His680Pro (c.2039A>C) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about MERTK p.His680Pro (c.2039A>C)?

AlphaMissense predicts likely pathogenic (score 0.9443) — an in-silico prediction, not a clinical call.

MERTK p.His680Pro

c.2039A>C · rs749028235 · VCV866314

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9443 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

MERTK-related disorder

Computational evidence

Protein change
AlphaMissense	0.9443	likely pathogenic · top 8% in MERTK
REVEL	0.549	indeterminate
SaProt	LLR -14.05	damaging
⇒ AlphaMissense and SaProt both call this damaging; 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	27.9	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) · 4/1,179,770 alleles

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

Overall 0.000274% 4/1,461,574 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.His680Pro
Coding: c.2039A>C
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

MERTK-related disorder

Similar variants

MERTK p.His680Arg Uncertain significance ★★ ⚠ same residue
MERTK p.His680Gln Uncertain significance ★★ ⚠ same residue
MERTK c.1605-2A>G Pathogenic ★★ same condition
MERTK c.1787-2A>T Pathogenic/Likely 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
MERTK p.Arg558Ter 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-his680pro (accessed [today's date]).

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