Is MERTK p.Ala220Ser (c.658G>T) pathogenic?

MERTK p.Ala220Ser (c.658G>T) is classified Uncertain significance in MERTK (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-31). AlphaMissense: ambiguous (0.4325); Very rare (popmax 0.0022%, sas).

How common is MERTK p.Ala220Ser (c.658G>T) in the general population?

MERTK p.Ala220Ser (c.658G>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about MERTK p.Ala220Ser (c.658G>T)?

AlphaMissense predicts ambiguous (score 0.4325) — an in-silico prediction, not a clinical call.

MERTK p.Ala220Ser

c.658G>T · rs1684980525 · VCV1373467

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4325 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Computational evidence

Protein change
AlphaMissense	0.4325	ambiguous
REVEL	0.345	indeterminate
SaProt	LLR -11.22	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 130 kb · p 0.00043 · regional, not allelic
Overall
CADD	27.7	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 0.0022% South Asian · 2/91,078 alleles

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

Overall 0.000205% 3/1,461,884 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,539
European (non-Finnish)	8.47e-05%	1,180,044

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.Ala220Ser
Coding: c.658G>T
MANE Select: NM_006343
dbSNP: rs1684980525
Type: single nucleotide variant
Location: chr2:111947468 (GRCh38)
Gene constraint: LOEUF 0.787 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.78 · 42 PDB
Residue 220: a disulfide bond; the ig-like c2-type 2 domain

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

Similar variants

MERTK p.Ala220Gly Uncertain significance ★★ same residue
MERTK p.Ala220Thr Uncertain significance ★ ⚠ same residue
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

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-ala220ser (accessed [today's date]).

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