Is MFRP p.Pro166Arg (c.497C>G) pathogenic?

MFRP p.Pro166Arg (c.497C>G) is classified Uncertain significance in MFRP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-30). AlphaMissense: likely benign (0.2582); Ultra-rare (popmax 0.03%, amr); Associated with isolated microphthalmia 5.

What condition is associated with MFRP p.Pro166Arg (c.497C>G)?

MFRP p.Pro166Arg (c.497C>G) is associated with isolated microphthalmia 5 (ClinVar).

How common is MFRP p.Pro166Arg (c.497C>G) in the general population?

MFRP p.Pro166Arg (c.497C>G) is ultra-rare (popmax 0.03%, amr) (gnomAD).

What do computational predictors say about MFRP p.Pro166Arg (c.497C>G)?

AlphaMissense predicts likely benign (score 0.2582) — an in-silico prediction, not a clinical call.

MFRP p.Pro166Arg

Q: How is Microphthalmia-retinitis pigmentosa-foveoschisis-optic disc drusen syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.497C>G · rs200251814 · VCV1013973

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2582 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.03%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

isolated microphthalmia 5

Computational evidence

Protein change
AlphaMissense	0.2582	likely benign
REVEL	0.218	benign-leaning
SaProt	LLR -11.11	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 6.5	GERP -0.88, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 4,962 bp · p 0.00017 · regional, not allelic
Overall
CADD	23.8	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 0.03% Admixed American · 18/59,978 alleles

Filtering AF 0.0194% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.016%

Overall 0.00415% 67/1,613,806 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.03%	3,332
African / African-American	0.00668%	14,980
Remaining individualsnot grpmax-eligible	0.0064%	15,622
European (non-Finnish)	0.00331%	30,256
South Asian	0.0011%	91,080

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: MFRP
Protein: p.Pro166Arg
Coding: c.497C>G
MANE Select: NM_001278431 · reported on NM_031433
dbSNP: rs200251814
Type: single nucleotide variant
Location: chr11:119345564 (GRCh38)

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

Disease context

isolated microphthalmia 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Microphthalmia-retinitis pigmentosa-foveoschisis-optic disc drusen syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Adult

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/mfrp-p-pro166arg (accessed [today's date]).

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