Is FLG2 p.Ser528Phe (c.1583C>T) pathogenic?

FLG2 p.Ser528Phe (c.1583C>T) is classified Uncertain significance in FLG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-28). AlphaMissense: ambiguous (0.3788); Ultra-rare (popmax 0.0164%, mid).

How common is FLG2 p.Ser528Phe (c.1583C>T) in the general population?

FLG2 p.Ser528Phe (c.1583C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about FLG2 p.Ser528Phe (c.1583C>T)?

AlphaMissense predicts ambiguous (score 0.3788) — an in-silico prediction, not a clinical call.

FLG2 p.Ser528Phe

c.1583C>T · VCV4025487

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3788 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

⚠ 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	0.3788	ambiguous
REVEL	0.024	moderately benign-leaning
SaProt	LLR -11.84	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 4.2	GERP -0.22, phastCons 0.67
Regional constraint	o/e 0.96	unconstrained · MANE · 8,271 bp · p 0.039 · regional, not allelic
Overall
CADD	17.38	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 0.0164% Middle Eastern · 1/6,080 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00225%

Overall 0.00285% 46/1,613,458 alleles · ultra-rare exomes 42/1,461,540 · genomes 4/151,918 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,080
European (non-Finnish)	0.00339%	29,492
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
Remaining individualsnot grpmax-eligible	0.0032%	31,240
Admixed American	0.00167%	59,988
South Asian	0.0011%	91,058

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.Ser528Phe
Coding: c.1583C>T
MANE Select: NM_001014342
Type: single nucleotide variant
Location: chr1:152356203 (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-ser528phe (accessed [today's date]).

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