Is MERTK p.Ser660Arg (c.1978A>C) pathogenic?

MERTK p.Ser660Arg (c.1978A>C) is classified Uncertain significance in MERTK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-04). AlphaMissense: ambiguous (0.5212); Very rare (popmax 0.0011%, sas).

How common is MERTK p.Ser660Arg (c.1978A>C) in the general population?

MERTK p.Ser660Arg (c.1978A>C) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about MERTK p.Ser660Arg (c.1978A>C)?

AlphaMissense predicts ambiguous (score 0.5212) — an in-silico prediction, not a clinical call.

MERTK p.Ser660Arg

c.1978A>C · VCV4746427

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5212 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Computational evidence

Protein change
AlphaMissense	0.5212	ambiguous
REVEL	0.482	indeterminate
SaProt	LLR -8.75	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.4	GERP -0.7, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 130 kb · p 0.00043 · regional, not allelic
Overall
CADD	23.7	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 0.0011% South Asian · 1/91,052 alleles

Overall 6.2e-05% 1/1,612,510 alleles · very rare exomes 1/1,460,198 · genomes 0/152,312 · joint denominator

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.Ser660Arg
Coding: c.1978A>C
MANE Select: NM_006343
Type: single nucleotide variant
Location: chr2:112009965 (GRCh38)
Gene constraint: LOEUF 0.787 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.78 · 42 PDB
Residue 660: the protein kinase domain

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-ser660arg (accessed [today's date]).

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