Is HCFC1 p.Val1237Phe (c.3709G>T) pathogenic?

HCFC1 p.Val1237Phe (c.3709G>T) is classified Uncertain significance in HCFC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-03-10). AlphaMissense: likely benign (0.0832); Very rare (popmax 0.00223%, amr); Associated with Inborn genetic diseases.

What condition is associated with HCFC1 p.Val1237Phe (c.3709G>T)?

HCFC1 p.Val1237Phe (c.3709G>T) is associated with Inborn genetic diseases (ClinVar).

How common is HCFC1 p.Val1237Phe (c.3709G>T) in the general population?

HCFC1 p.Val1237Phe (c.3709G>T) is very rare (popmax 0.00223%, amr) (gnomAD).

What do computational predictors say about HCFC1 p.Val1237Phe (c.3709G>T)?

AlphaMissense predicts likely benign (score 0.0832) — an in-silico prediction, not a clinical call.

HCFC1 p.Val1237Phe

c.3709G>T · VCV4841044

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0832 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0832	likely benign
REVEL	0.033	moderately benign-leaning
SaProt	LLR -8.31	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.35	GERP -2.7, phastCons 0.1
Regional constraint	o/e 0.91	unconstrained · MANE · 2,863 bp · p 0.028 · regional, not allelic
Overall
CADD	3.989	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% Admixed American · 1/44,902 alleles

Overall 0.000166% 2/1,203,132 alleles · very rare exomes 1/1,090,117 · genomes 1/113,015 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00223%	44,902
African / African-American	0.00174%	57,431

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.Val1237Phe
Coding: c.3709G>T
MANE Select: NM_005334
Type: single nucleotide variant
Location: chrX:153954690 (GRCh38)
Structure: AlphaFold pLDDT 47.89 · 11 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HCFC1 p.Asn1465Ser Uncertain significance ★★ ⚠ same condition
HCFC1 p.Asp1227Glu Uncertain significance ★★ ⚠ same condition
HCFC1 p.Gln1414His Uncertain significance ★★ ⚠ same condition
HCFC1 p.Gln1579Glu Uncertain significance ★★ ⚠ same condition
HCFC1 p.Gly1115Val Uncertain significance ★★ ⚠ same condition
HCFC1 p.Gly1553Glu Uncertain significance ★★ ⚠ same condition
HCFC1 p.Met2018Val Uncertain significance ★★ ⚠ same condition
HCFC1 p.Ser411Phe 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-val1237phe (accessed [today's date]).

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