Is UPF1 p.Pro649= (c.1947C>T) pathogenic?

UPF1 p.Pro649= (c.1947C>T) is classified Likely benign in UPF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-17). Very rare (popmax 0.00223%, eas).

How common is UPF1 p.Pro649= (c.1947C>T) in the general population?

UPF1 p.Pro649= (c.1947C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

UPF1 p.Pro649=

c.1947C>T · rs760440630 · VCV3186760

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6.5	GERP -2.3
Overall
CADD	8.32	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,880 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.00136% 22/1,612,276 alleles · very rare exomes 20/1,460,110 · genomes 2/152,166 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,880
European (non-Finnish)	0.00161%	62,086
Finnishnot grpmax-eligible	0.00157%	63,510
African / African-American	0.00134%	74,896

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: UPF1
Protein: p.Pro649=
Coding: c.1947C>T
MANE Select: NM_002911
dbSNP: rs760440630
Type: single nucleotide variant
Location: chr19:18856999 (GRCh38)
Gene constraint: LOEUF 0.125 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.58 · 12 PDB
Residue 649: an α-helix; the upf1-type sf1b helicase atp-binding domain

Full UPF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

UPF1 p.Pro649Leu Uncertain significance ★ ⚠ same residue
UPF1 c.1266-32T>G Benign ★★ same type
UPF1 c.1544+108G>A Benign ★★ same type
UPF1 c.2300+75T>C Benign ★★ same type
UPF1 c.232-90G>A Benign ★★ same type
UPF1 c.2457+89G>A Benign ★★ same type
UPF1 c.2458-85G>T Benign ★★ same type
UPF1 c.2601-188G>C Benign ★★ 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/upf1-p-pro649 (accessed [today's date]).

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