Is MERTK p.Lys274Arg (c.821A>G) pathogenic?

MERTK p.Lys274Arg (c.821A>G) is classified Uncertain significance in MERTK (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-22). AlphaMissense: likely benign (0.0667); Very rare (popmax 0.0022%, sas).

How common is MERTK p.Lys274Arg (c.821A>G) in the general population?

MERTK p.Lys274Arg (c.821A>G) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about MERTK p.Lys274Arg (c.821A>G)?

AlphaMissense predicts likely benign (score 0.0667) — an in-silico prediction, not a clinical call.

MERTK p.Lys274Arg

c.821A>G · rs774835500 · VCV1446017

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0667 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0667	likely benign
REVEL	0.014	strongly benign-leaning
SaProt	LLR -6.63	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 1.5	GERP 0.39, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 130 kb · p 0.00043 · regional, not allelic
Overall
CADD	13.46	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 0.0022% South Asian · 2/91,080 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000248% 4/1,614,208 alleles · very rare exomes 4/1,461,864 · genomes 0/152,344 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,540
European (non-Finnish)	0.000169%	590,012

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.Lys274Arg
Coding: c.821A>G
MANE Select: NM_006343
dbSNP: rs774835500
Type: single nucleotide variant
Location: chr2:111965254 (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 c.1296+1G>A Pathogenic/Likely pathogenic ★★ same type
MERTK c.1605-2A>G Pathogenic ★★ same type
MERTK c.1787-2A>T Pathogenic/Likely pathogenic ★★ same type
MERTK c.1867+1G>A Likely pathogenic ★★ same type
MERTK c.1868-1G>A Pathogenic ★★ same type
MERTK c.2189+1G>T Pathogenic ★★ same type
MERTK p.Ala768Thr Pathogenic/Likely pathogenic ★★ same type
MERTK p.Ala768Val Likely pathogenic ★★ 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-lys274arg (accessed [today's date]).

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