Is MERTK p.Asp774His (c.2320G>C) pathogenic?

MERTK p.Asp774His (c.2320G>C) is classified Uncertain significance in MERTK (ClinVar, Single submitter, 2 submitters; last evaluated 2021-10-23). AlphaMissense: likely pathogenic (0.9136); Ultra-rare (popmax 0.0285%, amr).

How common is MERTK p.Asp774His (c.2320G>C) in the general population?

MERTK p.Asp774His (c.2320G>C) is ultra-rare (popmax 0.0285%, amr) (gnomAD).

What do computational predictors say about MERTK p.Asp774His (c.2320G>C)?

AlphaMissense predicts likely pathogenic (score 0.9136) — an in-silico prediction, not a clinical call.

MERTK p.Asp774His

c.2320G>C · rs776309058 · VCV1352725

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9136 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0285%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9136	likely pathogenic · top 10% in MERTK
REVEL	0.619	indeterminate
SaProt	LLR -9.12	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 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 130 kb · p 0.00043 · regional, not allelic
Overall
CADD	32.0	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 0.0285% Admixed American · 16/56,166 alleles

Filtering AF 0.0178% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0145%

Overall 0.00103% 16/1,560,916 alleles · ultra-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.Asp774His
Coding: c.2320G>C
MANE Select: NM_006343
dbSNP: rs776309058
Type: single nucleotide variant
Location: chr2:112021552 (GRCh38)
Gene constraint: LOEUF 0.787 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.78 · 42 PDB
Residue 774: 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-asp774his (accessed [today's date]).

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