Is SURF1 p.Pro33Ala (c.97C>G) pathogenic?

SURF1 p.Pro33Ala (c.97C>G) is classified Uncertain significance in SURF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-01). AlphaMissense: likely benign (0.0606); Very rare (popmax 0.00981%, eas); Associated with Leigh syndrome.

What condition is associated with SURF1 p.Pro33Ala (c.97C>G)?

SURF1 p.Pro33Ala (c.97C>G) is associated with Leigh syndrome (ClinVar).

How common is SURF1 p.Pro33Ala (c.97C>G) in the general population?

SURF1 p.Pro33Ala (c.97C>G) is very rare (popmax 0.00981%, eas) (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.Pro33Ala (c.97C>G)?

AlphaMissense predicts likely benign (score 0.0606) — an in-silico prediction, not a clinical call.

SURF1 p.Pro33Ala

c.97C>G · rs1295640591 · VCV1020618

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0606 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00981%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Leigh syndrome

Computational evidence

Protein change
AlphaMissense	0.0606	likely benign
REVEL	0.15	moderately benign-leaning
SaProt	LLR -6.78	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 -0.75	GERP -2.5
Regional constraint	o/e 1.19	unconstrained · MANE · 4,537 bp · p 0.00027 · regional, not allelic
Overall
CADD	0.724	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 0.00981% East Asian · 4/40,756 alleles

Filtering AF 0.00329% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00194%

Overall 0.00241% 37/1,532,760 alleles · very rare exomes 37/1,380,574 · genomes 0/152,186 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00981%	10,189
European (non-Finnish)	0.00279%	35,815
Remaining individualsnot grpmax-eligible	0.00167%	59,764

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.Pro33Ala
Coding: c.97C>G
MANE Select: NM_003172
dbSNP: rs1295640591
Type: single nucleotide variant
Location: chr9:133356278 (GRCh38)
Gene constraint: LOEUF 1.559 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 82.62

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.Pro33Arg Uncertain significance ★ ⚠ 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-pro33ala (accessed [today's date]).

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