Is FLG p.Arg464His (c.1391G>A) pathogenic?

FLG p.Arg464His (c.1391G>A) is classified Likely benign in FLG (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-11). AlphaMissense: likely benign (0.0745); Ultra-rare (popmax 0.029%, eas); Associated with Inborn genetic diseases.

What condition is associated with FLG p.Arg464His (c.1391G>A)?

FLG p.Arg464His (c.1391G>A) is associated with Inborn genetic diseases (ClinVar).

How common is FLG p.Arg464His (c.1391G>A) in the general population?

FLG p.Arg464His (c.1391G>A) is ultra-rare (popmax 0.029%, eas) (gnomAD).

What do computational predictors say about FLG p.Arg464His (c.1391G>A)?

AlphaMissense predicts likely benign (score 0.0745) — an in-silico prediction, not a clinical call.

FLG p.Arg464His

c.1391G>A · VCV4025364

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0745 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.029%, eas)

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	0.0745	likely benign
REVEL	0.024	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 -0.76	GERP -2.1
Regional constraint	o/e 1.77	unconstrained · MANE · 8,404 bp · p 0 · regional, not allelic
Overall
CADD	0.021	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 0.029% East Asian · 13/44,830 alleles

Filtering AF 0.0171% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.00223% 36/1,613,808 alleles · ultra-rare exomes 34/1,461,870 · genomes 2/151,938 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.029%	3,448
European (non-Finnish)	0.00186%	53,637
Admixed American	0.00167%	59,992

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.Arg464His
Coding: c.1391G>A
MANE Select: NM_002016
Type: single nucleotide variant
Location: chr1:152313495 (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-arg464his (accessed [today's date]).

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