Is HCFC1 p.Pro7= (c.21C>T) pathogenic?

HCFC1 p.Pro7= (c.21C>T) is classified Likely benign in HCFC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-14). Very rare (popmax 0.000228%, nfe); Associated with methylmalonic acidemia with homocystinuria, type cblX.

What condition is associated with HCFC1 p.Pro7= (c.21C>T)?

HCFC1 p.Pro7= (c.21C>T) is associated with methylmalonic acidemia with homocystinuria, type cblX (ClinVar).

How common is HCFC1 p.Pro7= (c.21C>T) in the general population?

HCFC1 p.Pro7= (c.21C>T) is very rare (popmax 0.000228%, nfe) (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.Pro7=

c.21C>T · rs1557119928 · VCV2965406

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000228%, nfe)

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	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.1	GERP 0.11, phastCons 1
Overall
CADD	11.83	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000228% European (non-Finnish) · 2/876,648 alleles

Filtering AF 3.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.4e-05%

Overall 0.000171% 2/1,167,248 alleles · very rare exomes 2/1,053,629 · genomes 0/113,619 · joint denominator

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.Pro7=
Coding: c.21C>T
MANE Select: NM_005334
dbSNP: rs1557119928
Type: single nucleotide variant
Location: chrX:153970820 (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-pro7 (accessed [today's date]).

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