Is FLNA p.Pro17Ser (c.49C>T) pathogenic?

FLNA p.Pro17Ser (c.49C>T) is classified Uncertain significance in FLNA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-23). AlphaMissense: likely benign (0.0627); Very rare (popmax 0.00349%, afr); Associated with heterotopia, periventricular, X-linked dominant.

What condition is associated with FLNA p.Pro17Ser (c.49C>T)?

FLNA p.Pro17Ser (c.49C>T) is associated with heterotopia, periventricular, X-linked dominant, otopalatodigital syndrome type 2, Melnick-Needles syndrome (ClinVar).

How common is FLNA p.Pro17Ser (c.49C>T) in the general population?

FLNA p.Pro17Ser (c.49C>T) is very rare (popmax 0.00349%, afr) (gnomAD).

What do computational predictors say about FLNA p.Pro17Ser (c.49C>T)?

AlphaMissense predicts likely benign (score 0.0627) — an in-silico prediction, not a clinical call.

FLNA p.Pro17Ser

c.49C>T · rs1229353720 · VCV1955612

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0627 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00349%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

heterotopia, periventricular, X-linked dominant

Computational evidence

Protein change
AlphaMissense	0.0627	likely benign
REVEL	0.172	moderately benign-leaning
SaProt	LLR -5.77	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 1.3	GERP 1.5, phastCons 0.004
Regional constraint	o/e 2.09	unconstrained · MANE · 79 bp · p 1e-08 · regional, not allelic
Overall
CADD	20.2	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 0.00349% African / African-American · 2/57,384 alleles

Filtering AF 0.000578% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000216%

Overall 0.000251% 3/1,195,441 alleles · very rare exomes 1/1,082,537 · genomes 2/112,904 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00349%	28,692
European (non-Finnish)	0.000113%	888,423

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: FLNA
Protein: p.Pro17Ser
Coding: c.49C>T
MANE Select: NM_001110556
dbSNP: rs1229353720
Type: single nucleotide variant
Location: chrX:154371197 (GRCh38)
Structure: AlphaFold pLDDT 77.37 · 26 PDB
Residue 17: the 'disordered' region; the 'actin-binding' region

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

Disease context

heterotopia, periventricular, X-linked dominant — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: otopalatodigital syndrome type 2 Melnick-Needles syndrome frontometaphyseal dysplasia

Similar variants

FLNA p.Pro17Ala Likely benign ★ same residue
FLNA p.Pro17Leu Uncertain significance ★★ ⚠ same residue
FLNA c.1066-1G>A Pathogenic/Likely pathogenic ★★ same condition
FLNA c.2022+1G>A Pathogenic ★★ same condition
FLNA c.4598+1G>A Pathogenic/Likely pathogenic ★★ same condition
FLNA c.5417-2A>G Likely pathogenic ★★ same condition
FLNA c.868+1G>A Likely pathogenic ★★ same condition
FLNA c.987+1G>A Likely pathogenic ★★ 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/flna-p-pro17ser (accessed [today's date]).

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