Is C2CD2L p.Ser171Phe (c.512C>T) pathogenic?

C2CD2L p.Ser171Phe (c.512C>T) is classified Uncertain significance in C2CD2L (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-11). AlphaMissense: likely pathogenic (0.5734); Very rare (popmax 8.48e-05%, nfe).

How common is C2CD2L p.Ser171Phe (c.512C>T) in the general population?

C2CD2L p.Ser171Phe (c.512C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about C2CD2L p.Ser171Phe (c.512C>T)?

AlphaMissense predicts likely pathogenic (score 0.5734) — an in-silico prediction, not a clinical call.

C2CD2L p.Ser171Phe

c.512C>T · VCV3483501

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5734 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5734	likely pathogenic
REVEL	0.279	benign-leaning
SaProt	LLR -8.63	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 8,511 bp · p 2.1e-05 · regional, not allelic
Overall
CADD	27.2	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 8.48e-05% European (non-Finnish) · 1/1,179,712 alleles

Overall 0.000124% 2/1,612,692 alleles · very rare exomes 2/1,460,442 · genomes 0/152,250 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,426
European (non-Finnish)grpmax	8.48e-05%	1,179,711

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: C2CD2L
Protein: p.Ser171Phe
Coding: c.512C>T
MANE Select: NM_001290474
Type: single nucleotide variant
Location: chr11:119110622 (GRCh38)
Gene constraint: LOEUF 0.494 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 64.75 · 1 PDB
Residue 171: a β-strand; the smp-lbd domain

Full C2CD2L gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C2CD2L c.451-8G>A Benign ★★ same type
C2CD2L p.Ala14Thr Uncertain significance ★ ⚠ same type
C2CD2L p.Ala173Thr Uncertain significance ★ ⚠ same type
C2CD2L p.Ala245Ser Uncertain significance ★ ⚠ same type
C2CD2L p.Ala245Thr Uncertain significance ★ ⚠ same type
C2CD2L p.Ala326Val Uncertain significance ★ ⚠ same type
C2CD2L p.Ala512Val Uncertain significance ★ ⚠ same type
C2CD2L p.Ala524Thr Uncertain significance ★ ⚠ same type

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/c2cd2l-p-ser171phe (accessed [today's date]).

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