Is NFASC p.Pro8Ser (c.22C>T) pathogenic?

NFASC p.Pro8Ser (c.22C>T) is classified Conflicting classifications of pathogenicity in NFASC (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-09). Rare (popmax 0.365%, sas); Associated with Inborn genetic diseases.

What condition is associated with NFASC p.Pro8Ser (c.22C>T)?

NFASC p.Pro8Ser (c.22C>T) is associated with Inborn genetic diseases, neurodevelopmental disorder with central and peripheral motor dysfunction (ClinVar).

How common is NFASC p.Pro8Ser (c.22C>T) in the general population?

NFASC p.Pro8Ser (c.22C>T) is rare (popmax 0.365%, sas) (gnomAD).

NFASC p.Pro8Ser

c.22C>T · rs375852982 · VCV1805234

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.365%, sas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.049	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 2.6, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 53 kb · p 8.7e-18 · regional, not allelic
Overall
CADD	21.0	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.365% South Asian · 332/90,978 alleles

Filtering AF 0.333% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.32%

Overall 0.033% 532/1,613,840 alleles · rare exomes 485/1,461,520 · genomes 47/152,320 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.365%	274
Middle Eastern	0.199%	502
Remaining individualsnot grpmax-eligible	0.056%	1,785
European (non-Finnish)	0.0119%	8,368
Admixed American	0.0117%	8,572
African / African-American	0.004%	25,020
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,586
East Asian	0.00223%	44,868

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: NFASC
Protein: p.Pro8Ser
Coding: c.22C>T
MANE Select: NM_001005388
dbSNP: rs375852982
Type: single nucleotide variant
Location: chr1:204944337 (GRCh38)
Gene constraint: LOEUF 0.362 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.23 · 2 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: neurodevelopmental disorder with central and peripheral motor dysfunction

Similar variants

NFASC c.2593+5G>A Uncertain significance ★★ same condition
NFASC p.Ala253Thr Uncertain significance ★★ same condition
NFASC p.Arg133His Uncertain significance ★★ same condition
NFASC p.Arg436Gln Uncertain significance ★★ same condition
NFASC p.Asn655Asp Uncertain significance ★★ same condition
NFASC p.Asp1038Ala Uncertain significance ★★ same condition
NFASC p.Asp601Val Uncertain significance ★★ same condition
NFASC p.Gly23Arg 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/nfasc-p-pro8ser (accessed [today's date]).

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