Is FLNA p.Ala877Pro (c.2629G>C) pathogenic?

FLNA p.Ala877Pro (c.2629G>C) is classified Conflicting classifications of pathogenicity in FLNA (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-09-22). AlphaMissense: likely pathogenic (0.9693); Very rare (popmax 0.00434%, amr); Associated with heterotopia, periventricular, X-linked dominant.

What condition is associated with FLNA p.Ala877Pro (c.2629G>C)?

FLNA p.Ala877Pro (c.2629G>C) is associated with heterotopia, periventricular, X-linked dominant, otopalatodigital syndrome type 2, Melnick-Needles syndrome (ClinVar).

How common is FLNA p.Ala877Pro (c.2629G>C) in the general population?

FLNA p.Ala877Pro (c.2629G>C) is very rare (popmax 0.00434%, amr) (gnomAD).

What do computational predictors say about FLNA p.Ala877Pro (c.2629G>C)?

AlphaMissense predicts likely pathogenic (score 0.9693) — an in-silico prediction, not a clinical call.

FLNA p.Ala877Pro

c.2629G>C · rs377046577 · VCV1060042

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9693 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00434%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

heterotopia, periventricular, X-linked dominant

Computational evidence

Protein change
AlphaMissense	0.9693	likely pathogenic
REVEL	0.757	pathogenic-leaning
SaProt	LLR -13.37	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.29 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 6,571 bp · p 2.7e-08 · regional, not allelic
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00434% Admixed American · 2/46,099 alleles

Filtering AF 0.000719% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000269%

Overall 0.000248% 3/1,211,506 alleles · very rare exomes 3/1,097,653 · genomes 0/113,853 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00434%	23,049
European (non-Finnish)	0.000112%	895,423

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.Ala877Pro
Coding: c.2629G>C
MANE Select: NM_001110556
dbSNP: rs377046577
Type: single nucleotide variant
Location: chrX:154362269 (GRCh38)
Structure: AlphaFold pLDDT 77.37 · 26 PDB

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 familial thoracic aortic aneurysm and aortic dissection

Similar variants

FLNA p.Ala877= Likely benign ★★ same residue
FLNA p.Ala877Thr 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

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-ala877pro (accessed [today's date]).

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