Is UFL1 p.Ser28Pro (c.82T>C) pathogenic?

UFL1 p.Ser28Pro (c.82T>C) is classified Uncertain significance in UFL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-06). AlphaMissense: likely pathogenic (0.9718); Very rare (popmax 6.24e-05%).

How common is UFL1 p.Ser28Pro (c.82T>C) in the general population?

UFL1 p.Ser28Pro (c.82T>C) is very rare (popmax 6.24e-05%) (gnomAD).

What do computational predictors say about UFL1 p.Ser28Pro (c.82T>C)?

AlphaMissense predicts likely pathogenic (score 0.9718) — an in-silico prediction, not a clinical call.

UFL1 p.Ser28Pro

c.82T>C · VCV3977244

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9718 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.24e-05%)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9718	likely pathogenic · top 5% in UFL1
REVEL	0.828	moderately pathogenic-leaning
SaProt	LLR -15.80	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.8	GERP 1.4, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 32 kb · p 0.97 · regional, not allelic
Overall
CADD	28.2	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 6.24e-05%

Overall 6.24e-05% 1/1,601,808 alleles · very rare exomes 1/1,449,506 · genomes 0/152,302 · joint denominator

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.Ser28Pro
Coding: c.82T>C
MANE Select: NM_015323
Type: single nucleotide variant
Location: chr6:96523150 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.80 · 9 PDB
Residue 28: the 'required for e3 ufm1-protein ligase activity' region; the 'mediates interaction with ddrgk1' region

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

Similar variants

UFL1 p.Pro705Arg Uncertain significance ★★ ⚠ same type
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

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-ser28pro (accessed [today's date]).

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