Is UFL1 p.Pro705Arg (c.2114C>G) pathogenic?

UFL1 p.Pro705Arg (c.2114C>G) is classified Uncertain significance in UFL1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2020-08-01). AlphaMissense: likely pathogenic (0.9751); Rare (popmax 0.214%, mid); Associated with hereditary breast ovarian cancer syndrome.

What condition is associated with UFL1 p.Pro705Arg (c.2114C>G)?

UFL1 p.Pro705Arg (c.2114C>G) is associated with hereditary breast ovarian cancer syndrome (ClinVar).

How common is UFL1 p.Pro705Arg (c.2114C>G) in the general population?

UFL1 p.Pro705Arg (c.2114C>G) is rare (popmax 0.214%, mid) (gnomAD).

How is Hereditary breast and/or ovarian cancer syndrome inherited?

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

What do computational predictors say about UFL1 p.Pro705Arg (c.2114C>G)?

AlphaMissense predicts likely pathogenic (score 0.9751) — an in-silico prediction, not a clinical call.

UFL1 p.Pro705Arg

c.2114C>G · rs199880163 · VCV981816

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9751 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.214%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary breast ovarian cancer syndrome

Computational evidence

Protein change
AlphaMissense	0.9751	likely pathogenic · top 5% in UFL1
REVEL	0.622	indeterminate
SaProt	LLR -15.94	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 32 kb · p 0.97 · regional, not allelic
Overall
CADD	26.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.214% Middle Eastern · 13/6,078 alleles

Filtering AF 0.127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.1%

Overall 0.0111% 179/1,611,898 alleles · rare exomes 166/1,459,904 · genomes 13/151,994 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.214%	468
Finnishnot grpmax-eligible	0.0391%	2,556
Ashkenazi Jewishnot grpmax-eligible	0.0237%	4,215
Remaining individualsnot grpmax-eligible	0.0224%	4,456
South Asian	0.0188%	5,333
European (non-Finnish)	0.00856%	11,677
Admixed American	0.00168%	59,582
African / African-American	0.00134%	74,680

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: UFL1
Protein: p.Pro705Arg
Coding: c.2114C>G
MANE Select: NM_015323
dbSNP: rs199880163
Type: single nucleotide variant
Location: chr6:96552610 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.80 · 9 PDB

Full UFL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary breast ovarian cancer syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary breast and/or ovarian cancer syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

UFL1 p.Ala124Ser Uncertain significance ★ ⚠ same type
UFL1 p.Ala12Gly Uncertain significance ★ ⚠ same type
UFL1 p.Ala299Val Uncertain significance ★ ⚠ same type
UFL1 p.Ala353Ser Uncertain significance ★ ⚠ same type
UFL1 p.Ala648Val Uncertain significance ★ ⚠ same type
UFL1 p.Arg185Gly Uncertain significance ★ ⚠ same type
UFL1 p.Arg191Cys Uncertain significance ★ ⚠ same type
UFL1 p.Arg229Cys 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/ufl1-p-pro705arg (accessed [today's date]).

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