Is FLG p.Pro2557Ser (c.7669C>T) pathogenic?

FLG p.Pro2557Ser (c.7669C>T) is classified Likely benign in FLG (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-20). AlphaMissense: likely benign (0.0797); Ultra-rare (popmax 0.033%, mid); Associated with Inborn genetic diseases.

What condition is associated with FLG p.Pro2557Ser (c.7669C>T)?

FLG p.Pro2557Ser (c.7669C>T) is associated with Inborn genetic diseases (ClinVar).

How common is FLG p.Pro2557Ser (c.7669C>T) in the general population?

FLG p.Pro2557Ser (c.7669C>T) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about FLG p.Pro2557Ser (c.7669C>T)?

AlphaMissense predicts likely benign (score 0.0797) — an in-silico prediction, not a clinical call.

FLG p.Pro2557Ser

c.7669C>T · rs146352614 · VCV3095552

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0797 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

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	0.0797	likely benign
REVEL	0.013	strongly 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 -1.4	GERP -2
Regional constraint	o/e 1.77	unconstrained · MANE · 8,404 bp · p 0 · regional, not allelic
Overall
CADD	0.045	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 0.033% Middle Eastern · 2/6,060 alleles

Filtering AF 0.0199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.019%

Overall 0.0194% 312/1,612,346 alleles · ultra-rare exomes 286/1,461,476 · genomes 26/150,870 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,030
Remaining individualsnot grpmax-eligible	0.0256%	3,905
European (non-Finnish)	0.0221%	4,520
Admixed American	0.015%	6,657
African / African-American	0.0135%	7,387
South Asian	0.011%	9,106
East Asian	0.0067%	14,932
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,602

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.Pro2557Ser
Coding: c.7669C>T
MANE Select: NM_002016
dbSNP: rs146352614
Type: single nucleotide variant
Location: chr1:152307217 (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-pro2557ser (accessed [today's date]).

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