Is FLNA p.Lys165= (c.495G>A) pathogenic?

FLNA p.Lys165= (c.495G>A) is classified Benign in FLNA (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-20). Very rare (popmax 0.00217%, amr); Associated with otopalatodigital syndrome type 2.

What condition is associated with FLNA p.Lys165= (c.495G>A)?

FLNA p.Lys165= (c.495G>A) is associated with otopalatodigital syndrome type 2, heterotopia, periventricular, X-linked dominant, Melnick-Needles syndrome (ClinVar).

How common is FLNA p.Lys165= (c.495G>A) in the general population?

FLNA p.Lys165= (c.495G>A) is very rare (popmax 0.00217%, amr) (gnomAD).

FLNA p.Lys165=

c.495G>A · rs1569551873 · VCV2930783

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00217%, amr)

Conditions

otopalatodigital syndrome type 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.2	GERP 1.8
Overall
CADD	11.27	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00217% Admixed American · 1/46,082 alleles

Overall 0.000273% 3/1,097,773 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00217%	46,082
African / African-American	0.00173%	57,786
European (non-Finnish)	0.000112%	895,239

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.Lys165=
Coding: c.495G>A
MANE Select: NM_001110556
dbSNP: rs1569551873
Type: single nucleotide variant
Location: chrX:154367969 (GRCh38)
Structure: AlphaFold pLDDT 77.37 · 26 PDB
Residue 165: 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.Lys165Arg 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
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-lys165 (accessed [today's date]).

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