Is HCFC1 p.Ser623= (c.1869C>T) pathogenic?

HCFC1 p.Ser623= (c.1869C>T) is classified Benign/Likely benign in HCFC1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-06-01). Rare (popmax 0.16%, sas); Associated with methylmalonic acidemia with homocystinuria, type cblX.

What condition is associated with HCFC1 p.Ser623= (c.1869C>T)?

HCFC1 p.Ser623= (c.1869C>T) is associated with methylmalonic acidemia with homocystinuria, type cblX (ClinVar).

How common is HCFC1 p.Ser623= (c.1869C>T) in the general population?

HCFC1 p.Ser623= (c.1869C>T) is rare (popmax 0.16%, sas) (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.Ser623=

c.1869C>T · rs782463580 · VCV2723633

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.16%, sas)

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 -1.7	GERP -3.1
Overall
CADD	0.658	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.16% South Asian · 91/56,905 alleles

Filtering AF 0.133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.123%

Overall 0.00917% 111/1,210,778 alleles · rare exomes 107/1,097,795 · genomes 4/112,983 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.16%	625
Remaining individualsnot grpmax-eligible	0.0168%	5,953
East Asian	0.00296%	33,792
African / African-American	0.00174%	57,539
European (non-Finnish)	0.00112%	89,509

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.Ser623=
Coding: c.1869C>T
MANE Select: NM_005334
dbSNP: rs782463580
Type: single nucleotide variant
Location: chrX:153958184 (GRCh38)
Structure: AlphaFold pLDDT 47.89 · 11 PDB
Residue 623: the 'interaction with sin3a' region

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-ser623 (accessed [today's date]).

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