Is HCFC1 p.Pro985= (c.2955G>A) pathogenic?

HCFC1 p.Pro985= (c.2955G>A) is classified Likely benign in HCFC1 (ClinVar, Single submitter, 2 submitters; last evaluated 2026-01-21). Ultra-rare (popmax 0.0262%, afr); Associated with methylmalonic acidemia with homocystinuria, type cblX.

What condition is associated with HCFC1 p.Pro985= (c.2955G>A)?

HCFC1 p.Pro985= (c.2955G>A) is associated with methylmalonic acidemia with homocystinuria, type cblX (ClinVar).

How common is HCFC1 p.Pro985= (c.2955G>A) in the general population?

HCFC1 p.Pro985= (c.2955G>A) is ultra-rare (popmax 0.0262%, afr) (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.Pro985=

c.2955G>A · rs182541172 · VCV1569278

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0262%, afr)

Conditions

methylmalonic acidemia with homocystinuria, type cblX

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.26	acceptor gain · deltas
Constraint at this position
Conservation	phyloP -0.69	GERP -2.5
Overall
CADD	3.653	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0262% African / African-American · 15/57,354 alleles

Filtering AF 0.016% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.013%

Overall 0.00232% 28/1,207,700 alleles · ultra-rare exomes 18/1,095,181 · genomes 10/112,519 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0262%	3,824
Middle Eastern	0.023%	4,339
Admixed American	0.0131%	7,633
Remaining individualsnot grpmax-eligible	0.00632%	15,833
East Asian	0.00296%	33,766
European (non-Finnish)	0.000224%	446,834

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.Pro985=
Coding: c.2955G>A
MANE Select: NM_005334
dbSNP: rs182541172
Type: single nucleotide variant
Location: chrX:153955444 (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-pro985 (accessed [today's date]).

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