Is FLG p.Arg2139Gly (c.6415C>G) pathogenic?

FLG p.Arg2139Gly (c.6415C>G) is classified Uncertain significance in FLG (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-02). AlphaMissense: likely benign (0.1184); Very rare (popmax 0.00551%, nfe); Associated with Inborn genetic diseases.

What condition is associated with FLG p.Arg2139Gly (c.6415C>G)?

FLG p.Arg2139Gly (c.6415C>G) is associated with Inborn genetic diseases (ClinVar).

How common is FLG p.Arg2139Gly (c.6415C>G) in the general population?

FLG p.Arg2139Gly (c.6415C>G) is very rare (popmax 0.00551%, nfe) (gnomAD).

What do computational predictors say about FLG p.Arg2139Gly (c.6415C>G)?

AlphaMissense predicts likely benign (score 0.1184) — an in-silico prediction, not a clinical call.

FLG p.Arg2139Gly

c.6415C>G · rs758203305 · VCV3095521

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1184 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00551%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.1184	likely benign
REVEL	0.033	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -0.08	GERP -2.3
Regional constraint	o/e 1.77	unconstrained · MANE · 8,404 bp · p 0 · regional, not allelic
Overall
CADD	1.956	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00551% European (non-Finnish) · 65/1,179,846 alleles

Filtering AF 0.00443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00403%

Overall 0.00421% 68/1,613,576 alleles · very rare exomes 61/1,461,856 · genomes 7/151,720 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00551%	18,151
Remaining individualsnot grpmax-eligible	0.0048%	20,828

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: FLG
Protein: p.Arg2139Gly
Coding: c.6415C>G
MANE Select: NM_002016
dbSNP: rs758203305
Type: single nucleotide variant
Location: chr1:152308471 (GRCh38)

Full FLG 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

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/flg-p-arg2139gly (accessed [today's date]).

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