Is FLG p.Arg2139His (c.6416G>A) pathogenic?

FLG p.Arg2139His (c.6416G>A) is classified Likely benign in FLG (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-28). AlphaMissense: likely benign (0.0717); Ultra-rare (popmax 0.0461%, sas); Associated with Inborn genetic diseases.

What condition is associated with FLG p.Arg2139His (c.6416G>A)?

FLG p.Arg2139His (c.6416G>A) is associated with Inborn genetic diseases (ClinVar).

How common is FLG p.Arg2139His (c.6416G>A) in the general population?

FLG p.Arg2139His (c.6416G>A) is ultra-rare (popmax 0.0461%, sas) (gnomAD).

What do computational predictors say about FLG p.Arg2139His (c.6416G>A)?

AlphaMissense predicts likely benign (score 0.0717) — an in-silico prediction, not a clinical call.

FLG p.Arg2139His

c.6416G>A · rs200136954 · VCV3095522

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0717 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0461%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0717	likely benign
REVEL	0.009	strongly 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 -8.8	GERP -2.3
Overall
CADD	0.121	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0461% South Asian · 42/91,042 alleles

Filtering AF 0.035% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0311%

Overall 0.00446% 72/1,613,542 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0461%	2,168
East Asian	0.0223%	4,487
Remaining individualsnot grpmax-eligible	0.0096%	10,413
African / African-American	0.00401%	24,929
European (non-Finnish)	0.000932%	107,259

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.Arg2139His
Coding: c.6416G>A
dbSNP: rs200136954
Type: single nucleotide variant
Location: chr1:152308470 (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-arg2139his (accessed [today's date]).

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