Is GFER p.Phe186= (c.558C>T) pathogenic?

GFER p.Phe186= (c.558C>T) is classified Likely benign in GFER (ClinVar, Single submitter, 2 submitters; last evaluated 2025-12-17). Ultra-rare (popmax 0.048%, afr).

How common is GFER p.Phe186= (c.558C>T) in the general population?

GFER p.Phe186= (c.558C>T) is ultra-rare (popmax 0.048%, afr) (gnomAD).

GFER p.Phe186=

c.558C>T · rs142220504 · VCV2186348

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.048%, afr)

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 -0.47	GERP -3.1, phastCons 0.078
Overall
CADD	15.27	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.048% African / African-American · 36/75,068 alleles

Filtering AF 0.0356% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0313%

Overall 0.00397% 64/1,613,142 alleles · ultra-rare exomes 35/1,460,768 · genomes 29/152,374 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.048%	2,085
Admixed American	0.0366%	2,729
Remaining individualsnot grpmax-eligible	0.0032%	31,248
European (non-Finnish)	0.000339%	295,001

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: GFER
Protein: p.Phe186=
Coding: c.558C>T
MANE Select: NM_005262
dbSNP: rs142220504
Type: single nucleotide variant
Location: chr16:1985968 (GRCh38)
Gene constraint: LOEUF 1.87 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 78.50 · 7 PDB
Residue 186: the erv/alr sulfhydryl oxidase domain; an α-helix

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

Similar variants

GFER p.Arg194His Pathogenic ★★ same type
GFER p.Ser189Ter Pathogenic ★★ same type
GFER c.258+1G>A Uncertain significance ★★ same type
GFER p.Ala45Thr Uncertain significance ★★ ⚠ same type
GFER p.Ala46Val Uncertain significance ★★ ⚠ same type
GFER p.Ala73Ser Uncertain significance ★★ ⚠ same type
GFER p.Arg196Cys Uncertain significance ★★ ⚠ same type
GFER p.Arg82Gln 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/gfer-p-phe186 (accessed [today's date]).

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