Is GFER p.Ala46= (c.138C>T) pathogenic?

GFER p.Ala46= (c.138C>T) is classified Likely benign in GFER (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-18). Very rare (popmax 0.00563%, afr).

How common is GFER p.Ala46= (c.138C>T) in the general population?

GFER p.Ala46= (c.138C>T) is very rare (popmax 0.00563%, afr) (gnomAD).

GFER p.Ala46=

c.138C>T · rs936063405 · VCV1643906

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00563%, 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 -0.068	GERP -2
Overall
CADD	8.579	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00563% African / African-American · 4/70,996 alleles

Filtering AF 0.00192% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00109%

Overall 0.000264% 4/1,517,636 alleles · very rare exomes 1/1,365,488 · genomes 3/152,148 · 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: GFER
Protein: p.Ala46=
Coding: c.138C>T
MANE Select: NM_005262
dbSNP: rs936063405
Type: single nucleotide variant
Location: chr16:1984356 (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 46: the 'disordered' region

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

Similar variants

GFER p.Ala46Val Uncertain significance ★★ ⚠ same residue
GFER p.Ala46Pro Uncertain significance ★ ⚠ same residue
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.Ala73Ser Uncertain significance ★★ ⚠ same type
GFER p.Arg196Cys 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-ala46 (accessed [today's date]).

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