Is SURF1 p.Pro298Leu (c.893C>T) pathogenic?

SURF1 p.Pro298Leu (c.893C>T) is classified Conflicting classifications of pathogenicity in SURF1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-06-13). AlphaMissense: likely benign (0.1065); Very rare (popmax 8.48e-05%, nfe); Associated with Charcot-Marie-Tooth disease type 4K.

What condition is associated with SURF1 p.Pro298Leu (c.893C>T)?

SURF1 p.Pro298Leu (c.893C>T) is associated with Charcot-Marie-Tooth disease type 4K, mitochondrial complex IV deficiency, nuclear type 1 (ClinVar).

How common is SURF1 p.Pro298Leu (c.893C>T) in the general population?

SURF1 p.Pro298Leu (c.893C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

How is SURF1-related Charcot-Marie-Tooth disease type 4 inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about SURF1 p.Pro298Leu (c.893C>T)?

AlphaMissense predicts likely benign (score 0.1065) — an in-silico prediction, not a clinical call.

SURF1 p.Pro298Leu

c.893C>T · VCV3339531

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1065 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Charcot-Marie-Tooth disease type 4K

Computational evidence

Protein change
AlphaMissense	0.1065	likely benign
REVEL	0.425	indeterminate
SaProt	LLR -6.90	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.3	GERP 2.2, phastCons 1
Regional constraint	o/e 1.19	unconstrained · MANE · 4,537 bp · p 0.00027 · regional, not allelic
Overall
CADD	23.8	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,910 alleles

Overall 6.2e-05% 1/1,613,728 alleles · very rare exomes 1/1,461,410 · genomes 0/152,318 · 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: SURF1
Protein: p.Pro298Leu
Coding: c.893C>T
MANE Select: NM_003172
Type: single nucleotide variant
Location: chr9:133351923 (GRCh38)
Gene constraint: LOEUF 1.559 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 82.62
Residue 298: a UniProt-annotated variant site (in mc4dn1; uncertain significance)

Full SURF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Charcot-Marie-Tooth disease type 4K — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: mitochondrial complex IV deficiency, nuclear type 1

For SURF1-related Charcot-Marie-Tooth disease type 4 (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

SURF1 p.Pro298Arg Uncertain significance ★★ ⚠ same residue
SURF1 c.240+1G>T Pathogenic ★★ same condition
SURF1 c.324-11T>G Pathogenic/Likely pathogenic ★★ same condition
SURF1 c.516-1G>A Pathogenic ★★ same condition
SURF1 c.588+1G>C Pathogenic ★★ same condition
SURF1 c.833+1G>A Pathogenic ★★ same condition
SURF1 p.Arg192Gln Pathogenic/Likely pathogenic ★★ same condition
SURF1 p.Arg192Trp Pathogenic/Likely pathogenic ★★ 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/surf1-p-pro298leu (accessed [today's date]).

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