Is NFASC p.Pro716= (c.2148A>G) pathogenic?

NFASC p.Pro716= (c.2148A>G) is classified Benign in NFASC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2020-12-04). Common (popmax 21.8%, afr) — too common for a highly-penetrant pathogenic allele.

NFASC p.Pro716=

Q: How common is NFASC p.Pro716= (c.2148A>G) in the general population?

NFASC p.Pro716= (c.2148A>G) is common (popmax 21.8%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2148A>G · rs6667532 · VCV1247572

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 21.8%, afr) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.022	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8.4	GERP -4.5
Overall
CADD	0.695	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 21.8% African / African-American · 16,342/74,950 alleles

Filtering AF 21.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 21.4%

Overall 10.5% 169,036/1,613,570 alleles · common exomes 149,728/1,461,420 · genomes 19,308/152,150 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	21.8%	5
Middle Eastern	13.5%	7
European (non-Finnish)	10.6%	9
Ashkenazi Jewishnot grpmax-eligible	10.5%	10
Remaining individualsnot grpmax-eligible	10.3%	10
South Asian	8.53%	12
Finnishnot grpmax-eligible	7.77%	13
Admixed American	6.44%	16
Amishnot grpmax-eligible	3.18%	31
East Asian	2.28%	44

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.Pro716=
Coding: c.2148A>G
MANE Select: NM_001005388
dbSNP: rs6667532
Type: single nucleotide variant
Location: chr1:204979531 (GRCh38)
Gene constraint: LOEUF 0.362 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.23 · 2 PDB
Residue 716: the fibronectin type-iii 1 domain; the 'disordered' region

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

Similar variants

NFASC p.Pro716Leu Uncertain significance ★ same residue
NFASC c.2593+5G>A Uncertain significance ★★ same type
NFASC p.Ala253Thr Uncertain significance ★★ same type
NFASC p.Arg133His Uncertain significance ★★ same type
NFASC p.Arg436Gln Uncertain significance ★★ same type
NFASC p.Asn655Asp Uncertain significance ★★ same type
NFASC p.Asp1038Ala Uncertain significance ★★ same type
NFASC p.Asp601Val 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/nfasc-p-pro716 (accessed [today's date]).

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