Is FADS1 p.Pro46Arg (c.137C>G) pathogenic?

FADS1 p.Pro46Arg (c.137C>G) is classified Uncertain significance in FADS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-08). Ultra-rare (popmax 0.0446%, afr).

How common is FADS1 p.Pro46Arg (c.137C>G) in the general population?

FADS1 p.Pro46Arg (c.137C>G) is ultra-rare (popmax 0.0446%, afr) (gnomAD).

FADS1 p.Pro46Arg

c.137C>G · VCV4666068

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0446%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.018	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.76	GERP 0.39, phastCons 0.002
Regional constraint	o/e 1.10	unconstrained · MANE · 219 bp · p 0.26 · regional, not allelic
Overall
CADD	4.786	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0446% African / African-American · 31/69,576 alleles

Filtering AF 0.0322% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.028%

Overall 0.00206% 31/1,505,806 alleles · ultra-rare exomes 15/1,353,512 · genomes 16/152,294 · 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: FADS1
Protein: p.Pro46Arg
Coding: c.137C>G
MANE Select: NM_013402
Type: single nucleotide variant
Location: chr11:61816793 (GRCh38)
Gene constraint: LOEUF 0.428 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 94.82
Residue 46: the cytochrome b5 heme-binding domain

Full FADS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

FADS1 p.Ala221Val Uncertain significance ★ same type
FADS1 p.Ala229Thr Uncertain significance ★ same type
FADS1 p.Ala69Thr Uncertain significance ★ same type
FADS1 p.Arg178Trp Uncertain significance ★ same type
FADS1 p.Arg284His Uncertain significance ★ same type
FADS1 p.Arg28His Uncertain significance ★ same type
FADS1 p.Arg4His Uncertain significance ★ same type
FADS1 p.Asp61Asn 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/fads1-p-pro46arg (accessed [today's date]).

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