Is SURF1 p.Pro258fs (c.773_774del) pathogenic?

SURF1 p.Pro258fs (c.773774del) is classified Pathogenic in SURF1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-08-05). Very rare (popmax 0.00051%, nfe); Associated with Leigh syndrome.

What condition is associated with SURF1 p.Pro258fs (c.773_774del)?

SURF1 p.Pro258fs (c.773_774del) is associated with Leigh syndrome (ClinVar).

How common is SURF1 p.Pro258fs (c.773_774del) in the general population?

SURF1 p.Pro258fs (c.773_774del) is very rare (popmax 0.00051%, nfe) (gnomAD).

How is Leigh syndrome inherited?

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

SURF1 p.Pro258fs

c.773_774del · rs782237489 · VCV1705227

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00051%, nfe)

Conditions

Leigh syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 8 of 9
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -1.1	GERP -1.8, phastCons 0.002

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00051% European (non-Finnish) · 6/1,176,188 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000121%

Overall 0.000436% 7/1,606,474 alleles · very rare exomes 7/1,454,190 · genomes 0/152,284 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00161%	62,274
European (non-Finnish)grpmax	0.00051%	196,031

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro258fs
Coding: c.773_774del
MANE Select: NM_003172
dbSNP: rs782237489
Type: Deletion
Location: chr9:133352120 (GRCh38)
Gene constraint: LOEUF 1.559 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 82.62
Residue 258: a UniProt-annotated variant site (in mc4dn1; uncertain significance; reduces protein stability; impairs complex iv assembly); 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.Pro258_Gly261del Pathogenic ★★ same residue
SURF1 p.Pro258Arg Uncertain significance ★ ⚠ same residue
SURF1 p.Pro258Ser Pathogenic same residue
SURF1 c.515+1del Pathogenic/Likely pathogenic ★★ same condition
SURF1 p.Arg123fs Pathogenic ★★ same condition
SURF1 p.Asn269fs Pathogenic/Likely pathogenic ★★ same condition
SURF1 p.Gln251fs Pathogenic ★★ same condition
SURF1 p.Glu211fs 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-pro258fs (accessed [today's date]).

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