Is MERTK p.Pro33Ser (c.97C>T) pathogenic?

MERTK p.Pro33Ser (c.97C>T) is classified Uncertain significance in MERTK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-28). AlphaMissense: likely benign (0.0657); Ultra-rare (popmax 0.033%, mid); Associated with Inborn genetic diseases.

What condition is associated with MERTK p.Pro33Ser (c.97C>T)?

MERTK p.Pro33Ser (c.97C>T) is associated with Inborn genetic diseases (ClinVar).

How common is MERTK p.Pro33Ser (c.97C>T) in the general population?

MERTK p.Pro33Ser (c.97C>T) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about MERTK p.Pro33Ser (c.97C>T)?

AlphaMissense predicts likely benign (score 0.0657) — an in-silico prediction, not a clinical call.

MERTK p.Pro33Ser

c.97C>T · VCV4053877

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0657 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0657	likely benign
REVEL	0.09	moderately benign-leaning
SaProt	LLR -6.19	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 1.4	GERP 3.5, phastCons 0.001
Regional constraint	o/e 0.90	unconstrained · MANE · 130 kb · p 0.00043 · regional, not allelic
Overall
CADD	14.24	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 0.033% Middle Eastern · 2/6,062 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.00124% 20/1,614,120 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,031
South Asian	0.00659%	15,179
Admixed American	0.00167%	60,016
Remaining individualsnot grpmax-eligible	0.0016%	62,510
European (non-Finnish)	0.000847%	118,002

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.Pro33Ser
Coding: c.97C>T
MANE Select: NM_006343
Type: single nucleotide variant
Location: chr2:111929155 (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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MERTK p.Pro33= Likely benign ★★ same residue
MERTK p.Pro33Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
MERTK p.Ala29Gly Uncertain significance ★★ ⚠ same condition
MERTK p.Ala353Val Uncertain significance ★★ ⚠ same condition
MERTK p.Ala773Thr Uncertain significance ★★ ⚠ same condition
MERTK p.Ala944Thr Uncertain significance ★★ ⚠ same condition
MERTK p.Arg237Cys Uncertain significance ★★ ⚠ same condition
MERTK p.Arg557Gln Uncertain significance ★★ ⚠ same condition

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-pro33ser (accessed [today's date]).

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