Is ABRA p.Ser259Pro (c.775T>C) pathogenic?

ABRA p.Ser259Pro (c.775T>C) is classified Uncertain significance in ABRA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-08). AlphaMissense: likely pathogenic (0.8418); Ultra-rare (popmax 0.0329%, mid).

How common is ABRA p.Ser259Pro (c.775T>C) in the general population?

ABRA p.Ser259Pro (c.775T>C) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about ABRA p.Ser259Pro (c.775T>C)?

AlphaMissense predicts likely pathogenic (score 0.8418) — an in-silico prediction, not a clinical call.

ABRA p.Ser259Pro

c.775T>C · rs201763716 · VCV2220036

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8418 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8418	likely pathogenic
REVEL	0.089	moderately benign-leaning
SaProt	LLR -12.38	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP -1.1, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 9,150 bp · p 0.68 · regional, not allelic
Overall
CADD	21.7	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 0.0329% Middle Eastern · 2/6,082 alleles

Filtering AF 0.0136% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0129%

Overall 0.0135% 218/1,614,042 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,041
Remaining individualsnot grpmax-eligible	0.024%	4,166
European (non-Finnish)	0.0154%	6,484
South Asian	0.0132%	7,590
Admixed American	0.01%	9,999
African / African-American	0.00134%	74,904

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: ABRA
Protein: p.Ser259Pro
Coding: c.775T>C
MANE Select: NM_139166
dbSNP: rs201763716
Type: single nucleotide variant
Location: chr8:106761408 (GRCh38)
Gene constraint: LOEUF 0.993 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.14
Residue 259: the 'actin-binding 1' region; the 'interaction with actin' region

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

Similar variants

ABRA p.Ser259Phe Uncertain significance ★ ⚠ same residue
ABRA p.Ala37Val Uncertain significance ★ ⚠ same type
ABRA p.Ala62Thr Uncertain significance ★ ⚠ same type
ABRA p.Ala62Val Uncertain significance ★ ⚠ same type
ABRA p.Arg120Thr Uncertain significance ★ ⚠ same type
ABRA p.Arg149Ser Uncertain significance ★ ⚠ same type
ABRA p.Arg159Trp Uncertain significance ★ ⚠ same type
ABRA p.Arg203Lys Uncertain significance ★ ⚠ same type

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/abra-p-ser259pro (accessed [today's date]).

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