Is FLG2 p.His1908Arg (c.5723A>G) pathogenic?

FLG2 p.His1908Arg (c.5723A>G) is classified Uncertain significance in FLG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-23). AlphaMissense: likely benign (0.1457); Ultra-rare (popmax 0.033%, mid).

How common is FLG2 p.His1908Arg (c.5723A>G) in the general population?

FLG2 p.His1908Arg (c.5723A>G) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about FLG2 p.His1908Arg (c.5723A>G)?

AlphaMissense predicts likely benign (score 0.1457) — an in-silico prediction, not a clinical call.

FLG2 p.His1908Arg

c.5723A>G · rs147272606 · VCV2455335

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1457 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

⚠ 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	0.1457	likely benign
REVEL	0.032	moderately benign-leaning
SaProt	LLR -10.52	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 0.28	GERP 0.92
Regional constraint	o/e 0.96	unconstrained · MANE · 8,271 bp · p 0.039 · regional, not allelic
Overall
CADD	15.31	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.033% Middle Eastern · 2/6,060 alleles

Filtering AF 0.021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0178%

Overall 0.017% 275/1,613,792 alleles · ultra-rare exomes 252/1,461,868 · genomes 23/151,924 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,030
African / African-American	0.0307%	3,256
Remaining individualsnot grpmax-eligible	0.024%	4,167
European (non-Finnish)	0.0194%	5,153
Admixed American	0.00834%	11,995
East Asian	0.00223%	44,824

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: FLG2
Protein: p.His1908Arg
Coding: c.5723A>G
MANE Select: NM_001014342
dbSNP: rs147272606
Type: single nucleotide variant
Location: chr1:152352063 (GRCh38)

Full FLG2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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/flg2-p-his1908arg (accessed [today's date]).

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