Is MERTK p.Pro90His (c.269C>A) pathogenic?

MERTK p.Pro90His (c.269C>A) is classified Uncertain significance in MERTK (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-10). AlphaMissense: likely benign (0.0602); Ultra-rare (popmax 0.0329%, mid).

How common is MERTK p.Pro90His (c.269C>A) in the general population?

MERTK p.Pro90His (c.269C>A) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about MERTK p.Pro90His (c.269C>A)?

AlphaMissense predicts likely benign (score 0.0602) — an in-silico prediction, not a clinical call.

MERTK p.Pro90His

c.269C>A · rs199912096 · VCV1915529

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0602 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0602	likely benign
REVEL	0.129	moderately benign-leaning
SaProt	LLR -7.93	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 -0.79	GERP -2.5
Regional constraint	o/e 0.90	unconstrained · MANE · 130 kb · p 0.00043 · regional, not allelic
Overall
CADD	0.5	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 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.000496% 8/1,614,034 alleles · ultra-rare exomes 6/1,461,892 · genomes 2/152,142 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
Admixed American	0.00833%	11,999
European (non-Finnish)	8.47e-05%	1,180,025

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.Pro90His
Coding: c.269C>A
MANE Select: NM_006343
dbSNP: rs199912096
Type: single nucleotide variant
Location: chr2:111929327 (GRCh38)
Gene constraint: LOEUF 0.787 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.78 · 42 PDB
Residue 90: the ig-like c2-type 1 domain

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

Similar variants

MERTK p.Pro90Ser 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
MERTK p.Ala768Thr Pathogenic/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-pro90his (accessed [today's date]).

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