Is MYRF p.Pro263= (c.789C>G) pathogenic?

MYRF p.Pro263= (c.789C>G) is classified Benign in MYRF (ClinVar, Multiple submitters, 3 submitters; last evaluated 2019-06-10). Common (popmax 34.4%, mid) — too common for a highly-penetrant pathogenic allele.

MYRF p.Pro263=

Q: How common is MYRF p.Pro263= (c.789C>G) in the general population?

MYRF p.Pro263= (c.789C>G) is common (popmax 34.4%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.789C>G · rs149803 · VCV1233291

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 34.4%, mid) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.36	GERP -0.71, phastCons 0.99
Overall
CADD	7.924	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 34.4% Middle Eastern · 2,084/6,058 alleles

Filtering AF 33.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 32.7%

Overall 22.2% 358,693/1,613,810 alleles · common exomes 332,043/1,461,714 · genomes 26,650/152,096 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	46.9%	2
Ashkenazi Jewishnot grpmax-eligible	37.5%	3
Middle Easterngrpmax	34.4%	3
European (non-Finnish)	25.6%	4
Remaining individualsnot grpmax-eligible	21.5%	5
Finnishnot grpmax-eligible	18.5%	5
Admixed American	14.6%	7
South Asian	5.73%	17
African / African-American	4.55%	22
East Asian	0.0646%	1,547

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: MYRF
Protein: p.Pro263=
Coding: c.789C>G
MANE Select: NM_001127392
dbSNP: rs149803
Type: single nucleotide variant
Location: chr11:61771548 (GRCh38)
Gene constraint: LOEUF 0.215 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 61.76 · 2 PDB
Residue 263: a DNA-binding region

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

Similar variants

MYRF p.Pro263Arg Uncertain significance ★ ⚠ same residue
MYRF p.Gln150Ter Pathogenic/Likely pathogenic ★★ same type
MYRF p.Trp939Ter Pathogenic ★★ same type
MYRF p.Ala1001Ser Uncertain significance ★★ ⚠ same type
MYRF p.Arg174Cys Uncertain significance ★★ ⚠ same type
MYRF p.Arg733Gln Uncertain significance ★★ ⚠ same type
MYRF p.Asn267Ser Uncertain significance ★★ ⚠ same type
MYRF p.Glu421Lys Uncertain significance ★★ ⚠ 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/myrf-p-pro263 (accessed [today's date]).

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