Is FH p.Asp319= (c.957C>T) pathogenic?

FH p.Asp319= (c.957C>T) is classified Benign/Likely benign in FH (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-19). Ultra-rare (popmax 0.0133%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with FH p.Asp319= (c.957C>T)?

FH p.Asp319= (c.957C>T) is associated with hereditary neoplastic syndrome, hereditary leiomyomatosis and renal cell cancer (ClinVar).

How common is FH p.Asp319= (c.957C>T) in the general population?

FH p.Asp319= (c.957C>T) is ultra-rare (popmax 0.0133%, afr) (gnomAD).

FH p.Asp319=

c.957C>T · rs146751488 · VCV460383

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, afr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.037	GERP -5.6, phastCons 0.026
Overall
CADD	6.518	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0133% African / African-American · 10/74,910 alleles

Filtering AF 0.00723% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0055%

Overall 0.00217% 35/1,614,026 alleles · ultra-rare exomes 27/1,461,864 · genomes 8/152,162 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0133%	7,491
South Asian	0.0022%	45,542
European (non-Finnish)	0.00186%	53,637
Admixed American	0.00167%	60,000

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: FH
Protein: p.Asp319=
Coding: c.957C>T
MANE Select: NM_000143
dbSNP: rs146751488
Type: single nucleotide variant
Location: chr1:241504193 (GRCh38)
Gene constraint: LOEUF 0.599 · pLI 0.27 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 92.92 · 8 PDB
Residue 319: an α-helix

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary leiomyomatosis and renal cell cancer

Similar variants

FH p.Asp319Asn Uncertain significance ★★ ⚠ same residue
FH p.Asp319Tyr Likely pathogenic ★ same residue
FH p.Asp319Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
FH p.Asp319Val Conflicting classifications of pathogenicity ★ ⚠ same residue
FH p.Asp319_Ala320insAsp Conflicting classifications of pathogenicity ★ same residue
FH c.1108+1G>A Pathogenic ★★ same condition
FH c.1108+1G>T Pathogenic/Likely pathogenic ★★ same condition
FH c.1236+1G>A Pathogenic/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/fh-p-asp319 (accessed [today's date]).

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