Is FLG p.Pro478Ser (c.1432C>T) pathogenic?

FLG p.Pro478Ser (c.1432C>T) is classified Benign in FLG (ClinVar, Multiple submitters, 4 submitters; last evaluated 2023-04-11). AlphaMissense: likely benign (0.0409); Common (popmax 60.4%, eas) — too common for a highly-penetrant pathogenic allele; Associated with ichthyosis vulgaris.

What condition is associated with FLG p.Pro478Ser (c.1432C>T)?

FLG p.Pro478Ser (c.1432C>T) is associated with ichthyosis vulgaris (ClinVar).

What do computational predictors say about FLG p.Pro478Ser (c.1432C>T)?

AlphaMissense predicts likely benign (score 0.0409) — an in-silico prediction, not a clinical call.

FLG p.Pro478Ser

Q: How common is FLG p.Pro478Ser (c.1432C>T) in the general population?

FLG p.Pro478Ser (c.1432C>T) is common (popmax 60.4%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1432C>T · rs11584340 · VCV666623

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0409 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 60.4%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

ichthyosis vulgaris

Computational evidence

Protein change
AlphaMissense	0.0409	likely benign
REVEL	0.042	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.8	GERP -3.1
Overall
CADD	0.006	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 60.4% East Asian · 27,028/44,736 alleles

Filtering AF 59.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 59.6%

Overall 20.1% 324,266/1,613,236 alleles · common exomes 293,476/1,461,814 · genomes 30,790/151,422 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	60.4%	2
Admixed American	41.7%	2
South Asian	41.3%	2
Ashkenazi Jewishnot grpmax-eligible	30.4%	3
Middle Eastern	29.1%	3
Remaining individualsnot grpmax-eligible	23.6%	4
Amishnot grpmax-eligible	19.6%	5
Finnishnot grpmax-eligible	17.8%	6
European (non-Finnish)	15.9%	6
African / African-American	13.7%	7

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.Pro478Ser
Coding: c.1432C>T
MANE Select: NM_002016
dbSNP: rs11584340
Type: single nucleotide variant
Location: chr1:152313454 (GRCh38)
Gene constraint: LOEUF 1.932 · pLI <0.01 (gnomAD)
Residue 478: a UniProt-annotated variant site (in); the 'disordered' region

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

Disease context

ichthyosis vulgaris — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FLG p.Arg1798Ter Pathogenic/Likely pathogenic ★★ same condition
FLG p.Gln1790Ter Pathogenic ★★ same condition
FLG p.Gln355Ter Pathogenic ★★ same condition
FLG p.Ser2080Ter Pathogenic ★★ same condition
FLG p.Ser2554Ter Pathogenic/Likely pathogenic ★★ same condition
FLG p.Ser3296Ter Pathogenic ★★ same condition
FLG p.Arg1133Gln Uncertain significance ★★ ⚠ same condition
FLG p.Gln686Pro Uncertain significance ★★ ⚠ same condition

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-pro478ser (accessed [today's date]).

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