Is FLG2 p.Ala2139Ser (c.6415G>T) pathogenic?

FLG2 p.Ala2139Ser (c.6415G>T) is classified Uncertain significance in FLG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-25). AlphaMissense: likely benign (0.1034); Ultra-rare (popmax 0.0234%, amr).

How common is FLG2 p.Ala2139Ser (c.6415G>T) in the general population?

FLG2 p.Ala2139Ser (c.6415G>T) is ultra-rare (popmax 0.0234%, amr) (gnomAD).

What do computational predictors say about FLG2 p.Ala2139Ser (c.6415G>T)?

AlphaMissense predicts likely benign (score 0.1034) — an in-silico prediction, not a clinical call.

FLG2 p.Ala2139Ser

c.6415G>T · VCV4258130

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1034 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0234%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1034	likely benign
REVEL	0.042	moderately benign-leaning
SaProt	LLR -3.45	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -13	GERP -2.8
Regional constraint	o/e 0.96	unconstrained · MANE · 8,271 bp · p 0.039 · regional, not allelic
Overall
CADD	0.004	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 and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0234% Admixed American · 14/59,748 alleles

Filtering AF 0.0141% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0113%

Overall 0.000931% 15/1,611,556 alleles · ultra-rare exomes 13/1,461,862 · genomes 2/149,694 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0234%	4,268
European (non-Finnish)	8.48e-05%	1,179,423

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.Ala2139Ser
Coding: c.6415G>T
MANE Select: NM_001014342
Type: single nucleotide variant
Location: chr1:152351371 (GRCh38)
Gene constraint: LOEUF 1.934 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 33.09
Residue 2139: a UniProt-annotated variant site (in pss6; reduced protein abundance in patient's skin); the 'disordered' region

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

Similar variants

FLG2 p.His2208Tyr Uncertain significance ★★ ⚠ same type
FLG2 p.His1249Arg Benign ★★ same type
FLG2 p.Ala1450Pro Uncertain significance ★ ⚠ same type
FLG2 p.Asp50Gly Uncertain significance ★ ⚠ same type
FLG2 p.Gln1366Lys Uncertain significance ★ ⚠ same type
FLG2 p.Glu1274Gln Uncertain significance ★ ⚠ same type
FLG2 p.Gly1077Ser Uncertain significance ★ ⚠ same type
FLG2 p.Gly1697= Uncertain significance ★ same type

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-ala2139ser (accessed [today's date]).

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