Is SUMF1 p.Arg224Pro (c.671G>C) pathogenic?

SUMF1 p.Arg224Pro (c.671G>C) is classified Uncertain significance in SUMF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-09). AlphaMissense: likely pathogenic (0.989); Very rare (popmax 8.47e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SUMF1 p.Arg224Pro (c.671G>C)?

SUMF1 p.Arg224Pro (c.671G>C) is associated with Inborn genetic diseases (ClinVar).

How common is SUMF1 p.Arg224Pro (c.671G>C) in the general population?

SUMF1 p.Arg224Pro (c.671G>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about SUMF1 p.Arg224Pro (c.671G>C)?

AlphaMissense predicts likely pathogenic (score 0.989) — an in-silico prediction, not a clinical call.

SUMF1 p.Arg224Pro

c.671G>C · rs1357644781 · VCV3172095

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.989 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.989	likely pathogenic · top 5% in SUMF1
REVEL	0.894	moderately pathogenic-leaning
SaProt	LLR -17.09	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.8, phastCons 1
Regional constraint	o/e 1.18	unconstrained · MANE · 105 kb · p 0.0001 · regional, not allelic
Overall
CADD	32.0	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 8.47e-05% European (non-Finnish) · 1/1,180,008 alleles

Overall 6.2e-05% 1/1,614,030 alleles · very rare exomes 1/1,461,740 · genomes 0/152,290 · 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: SUMF1
Protein: p.Arg224Pro
Coding: c.671G>C
MANE Select: NM_182760
dbSNP: rs1357644781
Type: single nucleotide variant
Location: chr3:4418064 (GRCh38)
Gene constraint: LOEUF 1.254 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.39 · 21 PDB
Residue 224: a UniProt-annotated variant site (in msd; loss of activity)

Full SUMF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SUMF1 p.Arg224Gln Likely pathogenic ★★ same residue
SUMF1 p.Arg224Trp Pathogenic/Likely pathogenic ★★ same residue
SUMF1 p.Arg224= Uncertain significance same residue
SUMF1 p.Ala116Ser Uncertain significance ★★ ⚠ same condition
SUMF1 p.Ala214Val Uncertain significance ★★ ⚠ same condition
SUMF1 p.Arg369Cys Uncertain significance ★★ ⚠ same condition
SUMF1 p.Asp203His Uncertain significance ★★ ⚠ same condition
SUMF1 p.Leu6Val Uncertain significance ★★ ⚠ same condition

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/sumf1-p-arg224pro (accessed [today's date]).

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