Is FLNA p.Thr48Pro (c.142A>C) pathogenic?

FLNA p.Thr48Pro (c.142A>C) is classified Uncertain significance in FLNA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-02). AlphaMissense: likely pathogenic (0.9944); Absent from gnomAD v4.1; Associated with otopalatodigital syndrome type 2.

What condition is associated with FLNA p.Thr48Pro (c.142A>C)?

FLNA p.Thr48Pro (c.142A>C) is associated with otopalatodigital syndrome type 2, heterotopia, periventricular, X-linked dominant, Melnick-Needles syndrome (ClinVar).

How common is FLNA p.Thr48Pro (c.142A>C) in the general population?

FLNA p.Thr48Pro (c.142A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FLNA p.Thr48Pro (c.142A>C)?

AlphaMissense predicts likely pathogenic (score 0.9944) — an in-silico prediction, not a clinical call.

FLNA p.Thr48Pro

c.142A>C · rs2522771740 · VCV2001933

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9944 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

otopalatodigital syndrome type 2

Computational evidence

Protein change
AlphaMissense	0.9944	likely pathogenic · top 7% in FLNA
REVEL	0.954	strongly pathogenic-leaning
SaProt	LLR -16.03	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.8, phastCons 1
Regional constraint	o/e 0.30	constrained · MANE · 4,344 bp · p 1.3e-27 · regional, not allelic
Overall
CADD	28.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: FLNA
Protein: p.Thr48Pro
Coding: c.142A>C
MANE Select: NM_001110556
dbSNP: rs2522771740
Type: single nucleotide variant
Location: chrX:154371104 (GRCh38)
Structure: AlphaFold pLDDT 77.37 · 26 PDB
Residue 48: an α-helix; the calponin-homology (ch) 1 domain; the 'actin-binding' region

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

Disease context

otopalatodigital syndrome type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: heterotopia, periventricular, X-linked dominant Melnick-Needles syndrome frontometaphyseal dysplasia

Similar variants

FLNA p.Thr48= Likely benign ★★ 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
FLNA p.Ala1188Thr Pathogenic/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-thr48pro (accessed [today's date]).

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