Is SURF1 p.Pro298Arg (c.893C>G) pathogenic?

SURF1 p.Pro298Arg (c.893C>G) is classified Uncertain significance in SURF1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-05-04). AlphaMissense: likely benign (0.0641); Ultra-rare (popmax 0.0142%, nfe); Associated with Leigh syndrome.

What condition is associated with SURF1 p.Pro298Arg (c.893C>G)?

SURF1 p.Pro298Arg (c.893C>G) is associated with Leigh syndrome (ClinVar).

How common is SURF1 p.Pro298Arg (c.893C>G) in the general population?

SURF1 p.Pro298Arg (c.893C>G) is ultra-rare (popmax 0.0142%, nfe) (gnomAD).

How is Leigh syndrome inherited?

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

What do computational predictors say about SURF1 p.Pro298Arg (c.893C>G)?

AlphaMissense predicts likely benign (score 0.0641) — an in-silico prediction, not a clinical call.

SURF1 p.Pro298Arg

c.893C>G · rs201822068 · VCV526791

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0641 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0142%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Leigh syndrome

Computational evidence

Protein change
AlphaMissense	0.0641	likely benign
REVEL	0.441	indeterminate
SaProt	LLR -5.72	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
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	23.2	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 0.0142% European (non-Finnish) · 167/1,179,910 alleles

Filtering AF 0.0124% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0117%

Overall 0.0111% 179/1,613,728 alleles · ultra-rare exomes 165/1,461,410 · genomes 14/152,318 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0142%	7,065
Remaining individualsnot grpmax-eligible	0.0128%	7,812
Finnishnot grpmax-eligible	0.00469%	21,309
Admixed American	0.00167%	59,964

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.Pro298Arg
Coding: c.893C>G
MANE Select: NM_003172
dbSNP: rs201822068
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

Leigh syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Leigh syndrome (Orphanet):

Inheritance: Autosomal recessive, Mitochondrial inheritance, X-linked recessive
Onset: All ages
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

SURF1 p.Pro298Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
SURF1 c.106+1G>C Likely pathogenic ★★ same condition
SURF1 c.240+1G>T Pathogenic ★★ same condition
SURF1 c.324-11T>G Pathogenic/Likely pathogenic ★★ same condition
SURF1 c.516-2A>G Pathogenic ★★ same condition
SURF1 c.588+1G>C Pathogenic ★★ same condition
SURF1 c.751+1G>A Pathogenic ★★ same condition
SURF1 c.752-1G>C 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-pro298arg (accessed [today's date]).

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