Is MFRP p.Pro166Ser (c.496C>T) pathogenic?

MFRP p.Pro166Ser (c.496C>T) is classified Uncertain significance in MFRP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-11-22). AlphaMissense: likely benign (0.186); Very rare (popmax 0.00659%, sas); Associated with isolated microphthalmia 5.

What condition is associated with MFRP p.Pro166Ser (c.496C>T)?

MFRP p.Pro166Ser (c.496C>T) is associated with isolated microphthalmia 5 (ClinVar).

How common is MFRP p.Pro166Ser (c.496C>T) in the general population?

MFRP p.Pro166Ser (c.496C>T) is very rare (popmax 0.00659%, sas) (gnomAD).

What do computational predictors say about MFRP p.Pro166Ser (c.496C>T)?

AlphaMissense predicts likely benign (score 0.186) — an in-silico prediction, not a clinical call.

MFRP p.Pro166Ser

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.496C>T · rs145285193 · VCV834517

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.186 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00659%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

isolated microphthalmia 5

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.186	likely benign
REVEL	0.173	moderately benign-leaning
SaProt	LLR -8.12	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 3.3	GERP -2.8, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 4,962 bp · p 0.00017 · regional, not allelic
Overall
CADD	19.77	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 0.00659% South Asian · 6/91,084 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.000682% 11/1,613,936 alleles · very rare exomes 9/1,461,708 · genomes 2/152,228 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00659%	15,181
African / African-American	0.004%	24,979
East Asian	0.00223%	44,890
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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.Pro166Ser
Coding: c.496C>T
MANE Select: NM_031433
dbSNP: rs145285193
Type: single nucleotide variant
Location: chr11:119345565 (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-pro166ser (accessed [today's date]).

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