Is HCFC1 p.Pro990= (c.2970C>T) pathogenic?

HCFC1 p.Pro990= (c.2970C>T) is classified Likely benign in HCFC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-27). Absent from gnomAD v4.1; Associated with methylmalonic acidemia with homocystinuria, type cblX.

What condition is associated with HCFC1 p.Pro990= (c.2970C>T)?

HCFC1 p.Pro990= (c.2970C>T) is associated with methylmalonic acidemia with homocystinuria, type cblX (ClinVar).

How common is HCFC1 p.Pro990= (c.2970C>T) in the general population?

HCFC1 p.Pro990= (c.2970C>T) is absent from gnomAD v4.1 (gnomAD).

How is Methylmalonic acidemia with homocystinuria inherited?

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

HCFC1 p.Pro990=

c.2970C>T · rs2521569645 · VCV2704206

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

methylmalonic acidemia with homocystinuria, type cblX

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 2.9	GERP -0.87, phastCons 1
Overall
CADD	3.703	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: HCFC1
Protein: p.Pro990=
Coding: c.2970C>T
MANE Select: NM_005334
dbSNP: rs2521569645
Type: single nucleotide variant
Location: chrX:153955429 (GRCh38)
Structure: AlphaFold pLDDT 47.89 · 11 PDB

Full HCFC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

methylmalonic acidemia with homocystinuria, type cblX — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Methylmalonic acidemia with homocystinuria (Orphanet):

Inheritance: Autosomal recessive, X-linked recessive
Onset: All ages

Similar variants

HCFC1 p.Pro990Leu Uncertain significance ★ ⚠ same residue
HCFC1 p.Ala115Val Pathogenic ★★ same condition
HCFC1 c.2353+6G>A Uncertain significance ★★ same condition
HCFC1 c.503+6G>A Uncertain significance ★★ same condition
HCFC1 p.Ala1129Thr Uncertain significance ★★ ⚠ same condition
HCFC1 p.Ala1236Val Uncertain significance ★★ ⚠ same condition
HCFC1 p.Ala1526Thr Uncertain significance ★★ ⚠ same condition
HCFC1 p.Ala1597Thr 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/hcfc1-p-pro990 (accessed [today's date]).

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