Is GAS8 p.Met26Val (c.76A>G) pathogenic?

GAS8 p.Met26Val (c.76A>G) is classified Uncertain significance in GAS8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-10). AlphaMissense: likely benign (0.1684); Ultra-rare (popmax 0.0586%, afr); Associated with primary ciliary dyskinesia 33.

What condition is associated with GAS8 p.Met26Val (c.76A>G)?

GAS8 p.Met26Val (c.76A>G) is associated with primary ciliary dyskinesia 33 (ClinVar).

How common is GAS8 p.Met26Val (c.76A>G) in the general population?

GAS8 p.Met26Val (c.76A>G) is ultra-rare (popmax 0.0586%, afr) (gnomAD).

How is Primary ciliary dyskinesia inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about GAS8 p.Met26Val (c.76A>G)?

AlphaMissense predicts likely benign (score 0.1684) — an in-silico prediction, not a clinical call.

GAS8 p.Met26Val

c.76A>G · rs142699309 · VCV952479

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1684 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0586%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

primary ciliary dyskinesia 33

Computational evidence

Protein change
AlphaMissense	0.1684	likely benign
REVEL	0.174	moderately benign-leaning
SaProt	LLR -8.74	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 6.7	GERP 2, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 21 kb · p 0.0024 · regional, not allelic
Overall
CADD	21.4	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 0.0586% African / African-American · 44/75,042 alleles

Filtering AF 0.0448% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.04%

Overall 0.00322% 52/1,612,432 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0586%	1,706
Admixed American	0.005%	19,988
Remaining individualsnot grpmax-eligible	0.00481%	20,793
European (non-Finnish)	0.00017%	589,466

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: GAS8
Protein: p.Met26Val
Coding: c.76A>G
MANE Select: NM_001481
dbSNP: rs142699309
Type: single nucleotide variant
Location: chr16:90027708 (GRCh38)
Gene constraint: LOEUF 1.412 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.12 · 1 PDB
Residue 26: the 'regulates microtubule-binding' region; the 'disordered' region

Full GAS8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

primary ciliary dyskinesia 33 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Primary ciliary dyskinesia (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Neonatal
Prevalence: 1-5 / 10 000 (Pakistan)

Similar variants

GAS8 p.Met26Leu Uncertain significance ★ ⚠ same residue
DRC4 c.495+1G>T Likely pathogenic ★★ same condition
DRC4 p.Gln357Ter Pathogenic ★★ same condition
DRC4 p.Ala280Thr Uncertain significance ★★ ⚠ same condition
DRC4 p.Ala460Pro Uncertain significance ★★ ⚠ same condition
DRC4 p.Arg143Trp Uncertain significance ★★ ⚠ same condition
DRC4 p.Arg164Trp Uncertain significance ★★ ⚠ same condition
DRC4 p.Arg203Gln Uncertain significance ★★ ⚠ 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/gas8-p-met26val (accessed [today's date]).

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