Is GFER p.Pro141Ser (c.421C>T) pathogenic?

GFER p.Pro141Ser (c.421C>T) is classified Uncertain significance in GFER (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-05-01). AlphaMissense: likely pathogenic (0.9463); Ultra-rare (popmax 0.0822%, mid); Associated with Inborn genetic diseases.

What condition is associated with GFER p.Pro141Ser (c.421C>T)?

GFER p.Pro141Ser (c.421C>T) is associated with Inborn genetic diseases (ClinVar).

How common is GFER p.Pro141Ser (c.421C>T) in the general population?

GFER p.Pro141Ser (c.421C>T) is ultra-rare (popmax 0.0822%, mid) (gnomAD).

What do computational predictors say about GFER p.Pro141Ser (c.421C>T)?

AlphaMissense predicts likely pathogenic (score 0.9463) — an in-silico prediction, not a clinical call.

GFER p.Pro141Ser

c.421C>T · rs763545328 · VCV807350

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9463 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0822%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9463	likely pathogenic
REVEL	0.851	moderately pathogenic-leaning
SaProt	LLR -13.77	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 1.7, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 1,806 bp · p 0.23 · regional, not allelic
Overall
CADD	29.8	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 0.0822% Middle Eastern · 5/6,080 alleles

Filtering AF 0.0663% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0608%

Overall 0.00713% 115/1,613,500 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0822%	1,216
South Asian	0.0812%	1,231
Remaining individualsnot grpmax-eligible	0.0032%	31,238
European (non-Finnish)	0.0028%	35,754
East Asian	0.00223%	44,896

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.Pro141Ser
Coding: c.421C>T
MANE Select: NM_005262
dbSNP: rs763545328
Type: single nucleotide variant
Location: chr16:1984909 (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 141: the erv/alr sulfhydryl oxidase domain

Full GFER 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

GFER p.Ser189Ter Pathogenic ★★ same condition
GFER p.Ala45Thr Uncertain significance ★★ ⚠ same condition
GFER p.Ala46Val Uncertain significance ★★ ⚠ same condition
GFER p.Ala73Ser Uncertain significance ★★ ⚠ same condition
GFER p.Asn14Lys Uncertain significance ★★ ⚠ same condition
GFER p.Asp43Glu Uncertain significance ★★ ⚠ same condition
GFER p.Asp43Tyr Uncertain significance ★★ ⚠ same condition
GFER p.Cys204Arg 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/gfer-p-pro141ser (accessed [today's date]).

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