Is MERTK p.Asp869fs (c.2603dup) pathogenic?

MERTK p.Asp869fs (c.2603dup) is classified Uncertain significance in MERTK (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-10). Very rare (popmax 0.00364%, nfe).

How common is MERTK p.Asp869fs (c.2603dup) in the general population?

MERTK p.Asp869fs (c.2603dup) is very rare (popmax 0.00364%, nfe) (gnomAD).

MERTK p.Asp869fs

c.2603dup · rs751437121 · VCV1040493

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00364%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (19 of 19) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.5	GERP 0.86, phastCons 1
Overall
CADD	26.7	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00364% European (non-Finnish) · 43/1,180,046 alleles

Filtering AF 0.00275% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00244%

Overall 0.00285% 46/1,614,184 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00364%	27,443
Remaining individualsnot grpmax-eligible	0.0032%	31,254
African / African-American	0.00133%	75,026

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.Asp869fs
Coding: c.2603dup
MANE Select: NM_006343
dbSNP: rs751437121
Type: Duplication
Location: chr2:112028466 (GRCh38)
Gene constraint: LOEUF 0.787 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.78 · 42 PDB

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

Similar variants

MERTK p.Asp869= Likely benign ★ same residue
MERTK p.Ile930fs Uncertain significance ★★ same type
MERTK c.584-1_584dup Pathogenic ★ same type
MERTK p.Glu595fs Pathogenic ★ same type
MERTK p.Pro149fs Pathogenic ★ same type
MERTK p.Ser398fs Pathogenic ★ same type
MERTK p.Val276fs Pathogenic ★ same type
MERTK c.1296+2dup Conflicting classifications of pathogenicity ★ same type

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-asp869fs (accessed [today's date]).

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