Is SURF1 p.Pro258Ser (c.772C>T) pathogenic?

SURF1 p.Pro258Ser (c.772C>T) is classified Pathogenic in SURF1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2018-04-05). AlphaMissense: likely pathogenic (0.9652); Very rare (popmax 8.51e-05%, nfe); Associated with Leigh syndrome.

What condition is associated with SURF1 p.Pro258Ser (c.772C>T)?

SURF1 p.Pro258Ser (c.772C>T) is associated with Leigh syndrome (ClinVar).

How common is SURF1 p.Pro258Ser (c.772C>T) in the general population?

SURF1 p.Pro258Ser (c.772C>T) is very rare (popmax 8.51e-05%, 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.Pro258Ser (c.772C>T)?

AlphaMissense predicts likely pathogenic (score 0.9652) — an in-silico prediction, not a clinical call.

SURF1 p.Pro258Ser

c.772C>T · rs1053850536 · VCV520388

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9652 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.51e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Leigh syndrome

Computational evidence

Protein change
AlphaMissense	0.9652	likely pathogenic ✓ concordant with ClinVar · top 4% in SURF1
REVEL	0.895	moderately pathogenic-leaning
SaProt	LLR -13.03	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.8	GERP 2.1, phastCons 1
Regional constraint	o/e 1.19	unconstrained · MANE · 4,537 bp · p 0.00027 · regional, not allelic
Overall
CADD	26.2	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 8.51e-05% European (non-Finnish) · 1/1,175,358 alleles

Overall 6.23e-05% 1/1,605,014 alleles · very rare exomes 1/1,452,722 · genomes 0/152,292 · 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.Pro258Ser
Coding: c.772C>T
MANE Select: NM_003172
dbSNP: rs1053850536
Type: single nucleotide variant
Location: chr9:133352122 (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.Pro258Arg Uncertain significance ★ ⚠ same residue
SURF1 p.Pro258_Gly261del Pathogenic ★★ same residue
SURF1 p.Pro258fs Pathogenic ★★ 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

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-pro258ser (accessed [today's date]).

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