Is HCFC1 p.Ala596= (c.1788C>T) pathogenic?

HCFC1 p.Ala596= (c.1788C>T) is classified Likely benign in HCFC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-25). Very rare (popmax 0.00298%, eas); Associated with methylmalonic acidemia with homocystinuria, type cblX.

What condition is associated with HCFC1 p.Ala596= (c.1788C>T)?

HCFC1 p.Ala596= (c.1788C>T) is associated with methylmalonic acidemia with homocystinuria, type cblX (ClinVar).

How common is HCFC1 p.Ala596= (c.1788C>T) in the general population?

HCFC1 p.Ala596= (c.1788C>T) is very rare (popmax 0.00298%, eas) (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.Ala596=

c.1788C>T · rs1557115819 · VCV2971102

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00298%, eas)

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 1.3	GERP -0.71, phastCons 1
Overall
CADD	10.15	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00298% East Asian · 1/33,586 alleles

Overall 0.000167% 2/1,200,625 alleles · very rare exomes 1/1,087,827 · genomes 1/112,798 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00298%	33,586
African / African-American	0.00175%	57,249

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: HCFC1
Protein: p.Ala596=
Coding: c.1788C>T
MANE Select: NM_005334
dbSNP: rs1557115819
Type: single nucleotide variant
Location: chrX:153958584 (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.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
HCFC1 p.Ala1597Val 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-ala596 (accessed [today's date]).

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